Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting B-amyloid peptide release and/or its synthesis by use of such compounds

ABSTRACT

Disclosed are compounds which inhibit β-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer&#39;s disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits β-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer&#39;s disease both prophylactically and therapeutically with such pharmaceutical compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/064,851 which was converted pursuant to 37 C.F.R.§1.53(b)(2)(ii) from U.S. patent application Ser. No. 08/780,025, filedDec. 23, 1996.

FIELD OF THE INVENTION

[0002] This invention relates to compounds which inhibit β-amyloidpeptide release and/or its synthesis, and, accordingly, have utility intreating Alzheimer's disease.

REFERENCES

[0003] The following publications, patents and patent applications arecited in this application as superscript numbers:

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[0005] 2 U.S. Pat. No. 4,666,829

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[0101] All of the above publications, patents and patent applicationsare herein incorporated by reference in their entirety to the sameextent as if each individual publication, patent or patent applicationwas specifically and individually indicated to be incorporated byreference in its entirety.

State of the Art

[0102] Alzheimer's Disease (AD) is a degenerative brain disordercharacterized clinically by progressive loss of memory, cognition,reasoning, judgment and emotional stability that gradually leads toprofound mental deterioration and ultimately death. AD is a very commoncause of progressive mental failure (dementia) in aged humans and isbelieved to represent the fourth most common medical cause of death inthe United States. AD has been observed in races and ethnic groupsworldwide and presents a major present and future public health problem.The disease is currently estimated to affect about two to three millionindividuals in the United States alone. AD is at present incurable. Notreatment that effectively prevents AD or reverses its symptoms andcourse is currently known.

[0103] The brains of individuals with AD exhibit characteristic lesionstermed senile (or amyloid) plaques, amyloid angiopathy (amyloid depositsin blood vessels) and neurofibrillary tangles. Large numbers of theselesions, particularly amyloid plaques and neurofibrillary tangles, aregenerally found in several areas of the human brain important for memoryand cognitive function in patients with AD. Smaller numbers of theselesions in a more restrictive anatomical distribution are also found inthe brains of most aged humans who do not have clinical AD. Amyloidplaques and amyloid angiopathy also characterize the brains ofindividuals with Trisomy 21 (Down's Syndrome) and Hereditary CerebralHemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, adefinitive diagnosis of AD usually requires observing the aforementionedlesions in the brain tissue of patients who have died with the diseaseor, rarely, in small biopsied samples of brain tissue taken during aninvasive neurosurgical procedure.

[0104] The principal chemical constituent of the amyloid plaques andvascular amyloid deposits (amyloid angiopathy) characteristic of AD andthe other disorders mentioned above is an approximately 4.2 kilodalton(kD) protein of about 39-43 amino acids designated the β-amyloid peptide(βAP) or sometimes Aβ, AβP or β/A4. β-Amyloid peptide was first purifiedand a partial amino acid sequence was provided by Glenner, et al.¹ Theisolation procedure and the sequence data for the first 28 amino acidsare described in U.S. Pat. No. 4,666,829².

[0105] Molecular biological and protein chemical analyses have shownthat the β-amyloid peptide is a small fragment of a much largerprecursor protein termed the amyloid precursor protein (APP), that isnormally produced by cells in many tissues of various animals, includinghumans. Knowledge of the structure of the gene encoding APP hasdemonstrated that β-amyloid peptide arises as a peptide fragment that iscleaved from APP by protease enzyme(s). The precise biochemicalmechanism by which the β-amyloid peptide fragment is cleaved from APPand subsequently deposited as amyloid plaques in the cerebral tissue andin the walls of the cerebral and meningeal blood vessels is currentlyunknown.

[0106] Several lines of evidence indicate that progressive cerebraldeposition of β-amyloid peptide plays a seminal role in the pathogenesisof AD and can precede cognitive symptoms by years or decades. See, forexample, Selkoe³. The most important line of evidence is the discoverythat missense DNA mutations at amino acid 717 of the 770-amino acidisoform of APP can be found in affected members but not unaffectedmembers of several families with a genetically determined (familial)form of AD (Goate, et al.⁴; Chartier Harlan, et al.⁵; and Murrell, etal.⁶) and is referred to as the Swedish variant. A double mutationchanging lysine⁵⁹⁵-methionine⁵⁹⁶ to asparagine⁵⁹⁵-leucine⁵⁹⁶ (withreference to the 695 isoform) found in a Swedish family was reported in1992 (Mullan, et al.⁷). Genetic linkage analyses have demonstrated thatthese mutations, as well as certain other mutations in the APP gene, arethe specific molecular cause of AD in the affected members of suchfamilies. In addition, a mutation at amino acid 693 of the 770-aminoacid isoform of APP has been identified as the cause of the β-amyloidpeptide deposition disease, HCHWA-D, and a change from alanine toglycine at amino acid 692 appears to cause a phenotype that resembles ADis some patients but HCHWA-D in others. The discovery of these and othermutations in APP in genetically based cases of AD prove that alterationof APP and subsequent deposition of its β-amyloid peptide fragment cancause AD.

[0107] Despite the progress which has been made in understanding theunderlying mechanisms of AD and other β-amyloid peptide relateddiseases, there remains a need to develop methods and compositions fortreatment of the disease(s). Ideally, the treatment methods wouldadvantageously be based on drugs which are capable of inhibitingβ-amyloid peptide release and/or its synthesis in vivo.

SUMMARY OF THE INVENTION

[0108] This invention is directed to the discovery of a class ofcompounds which inhibit β-amyloid peptide release and/or its synthesisand, therefore, are useful in the prevention of AD in patientssusceptible to AD and/or in the treatment of patients with AD in orderto inhibit further deterioration in their condition. The class ofcompounds having the described properties are defined by formula Ibelow:

[0109] wherein R¹ is selected from the group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkenyl, substituted alkynyl, substituted cycloalkyl,substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;

[0110] W, together with —C(H)_(p)C(═X)—, forms a cycloalkyl,cycloalkenyl, heterocyclic, substituted cycloalkyl, or substitutedcycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl,heterocyclic, substituted cycloalkyl or substituted cycloalkenyl groupis optionally fused to form a bi- or multi-fused ring system (preferablyno more than 5 fused rings) with one or more ring structures selectedfrom the group consisting of cycloalkyl, cycloalkenyl, heterocyclic,aryl and heteroaryl group which, in turn, each of such ring structuresare optionally substituted with 1 to 4 substituents selected from thegroup consisting of hydroxyl, halo, alkoxy, substituted alkoxy,thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxylesters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino,N-substituted alkylamino, N-alkyl N-substituted alkylamino,N,N-disubstituted alkylamino, —NHC(O)R⁴, —NHSO₂R⁴, —C(O)NH₂, —C)NHR⁴,—(O)NR⁴R⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NHR⁴ and —S(O)₂NR⁴R⁴ where each R⁴is independently selected from the group consisting of alkyl,substituted alkyl, or aryl;

[0111] X is selected from the group consisting of oxo (═O), thiooxo(═S), hydroxyl (—H, —OH), thiol (H,—SH) and hydro (H,H);

[0112] Y is represented by the formula:

[0113] wherein each R² is independently selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclic;

[0114] Z is represented by the formula —T—CX′X″C(O)— where T is selectedfrom the group consisting of a bond covalently linking R¹ to —CX′X″—,oxygen, sulfur, —NR⁵ where R⁵ is hydrogen, acyl, alkyl, aryl orheteroaryl group;

[0115] X′ is hydrogen, hydroxy or fluoro,

[0116] X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form anoxo group;

[0117] m is an integer equal to 0 or 1;

[0118] n is an integer equal to 0, 1 or 2;

[0119] p is an integer equal to 0 or 1 such that when p is zero, thering defined by W and —C(H)_(p)C(═X)— is unsaturated at the carbon atomof ring attachment to Y and when p is one, the ring is saturated at thecarbon atom of ring attachment to Y,

[0120] with the following provisos:

[0121] A. when R¹ is 3,5-difluorophenyl, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a 2-(S)-indanol group;

[0122] B. when R¹ is phenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form atrans-2-hydroxy-cyclohex-1-yl group;

[0123] C. when R¹ is phenyl, Z is —CH₂C(O)—, m is 1, n is 0, and p is 1,then W, together with >CH and >C═X, does not form a gamma-butyrolactonegroup or a 5,5-dimethyl-gamma-butyrolactone group;

[0124] D. when R¹ is phenyl, Z is —CH₂C(O)—, m is 1, n is 0, and p is 1,then W, together with >CH and >C═X, does not form a E-caprolactam group;

[0125] E. when R¹ is cyclopropyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, nis 1, and p is 1, then W, together with >CH and >C═X, does not form anN-methylcaprolactam group;

[0126] F. when R¹ is 4-chlorobenzoyl-CH₂—, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform an 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one;

[0127] G. when R¹ is 2-phenylphenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1,n is 1, and p is 1, then W, together with >CH and >C═X, does not form an7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one;

[0128] H. when R¹ is CH₃OC(O)CH₂—, R² is —CH₃, Z is —CH₂C(O)—, m is 1, nis 1, and p is 1, then W, together with >CH and >C═X, does not form an2,3-dihydro-1-(t-butylC(O)CH₂-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;

[0129] I. when R¹ is 4-ethoxyphenyl, 2,4,6-trimethylphenyl,4-phenylphenyl, CH₃OC(O)CH₂—, 4-HOCH₂-phenyl, 2,4,6-trifluorophenyl,2-trifluoromethyl-4-fluorophenyl, or CH₃S—, R² is —CH₃, Z is —CH₂C(O)—,m is 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²—)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;

[0130] J. when R¹ is 2,6-difluorophenyl, R² is —CH₃, Z is —CH(OH)C(O)—,m is 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²—)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,

[0131] K. when m is 1 and n is 1, then

[0132] does not equal cycloalkyl of from 3 to 8 carbon atoms optionallysubstituted with 1 to 3 alkyl groups.

[0133] Accordingly, in one of its method aspects, this invention isdirected to a method for inhibiting β-amyloid peptide release and/or itssynthesis in a cell which method comprises administering to such a cellan amount of a compound or a mixture of compounds of formula I aboveeffective in inhibiting the cellular release and/or synthesis ofβ-amyloid peptide.

[0134] Because the in vivo generation of β-amyloid peptide is associatedwith the pathogenesis of AD^(8.9), the compounds of formula I can alsobe employed in conjunction with a pharmaceutical composition toprophylactically and/or therapeutically prevent and/or treat AD.Accordingly, in another of its method aspects, this invention isdirected to a prophylactic method for preventing the onset of AD in apatient at risk for developing AD which method comprises administeringto said patient a pharmaceutical composition comprising apharmaceutically inert carrier and an effective amount of a compound ora mixture of compounds of formula I above.

[0135] In yet another of its method aspects, this invention is directedto a therapeutic method for treating a patient with AD in order toinhibit further deterioration in the condition of that patient whichmethod comprises administering to said patient a pharmaceuticalcomposition comprising a pharmaceutically inert carrier and an effectiveamount of a compound or a mixture of compounds of formula I above.

[0136] In formula I above, when m is zero (i.e., there is a covalentbond from R¹ to NH), R¹ is preferably aryl (including substituted aryl)or heteroaryl (including substituted heteroaryl). In this embodiment,further preferred R¹ groups include

[0137] (a) phenyl,

[0138] (b) a substituted phenyl group of the formula:

[0139] wherein R^(c) is selected from the group consisting of acyl,alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro,trihalomethyl, thioalkoxy, and wherein R^(b) and R^(c) are fused to forma heteroaryl or heterocyclic ring with the phenyl ring wherein theheteroaryl or heterocyclic ring contains from 3 to 8 atoms of which from1 to 3 are heteroatoms independently selected from the group consistingof oxygen, nitrogen and sulfur

[0140] R^(b) and R^(b′) are independently selected from the groupconsisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, andthioalkoxy with the proviso that when R^(c) is hydrogen, then R^(b) andR^(b′) are either both hydrogen or both substituents other thanhydrogen,

[0141] (c) 2-naphthyl,

[0142] (d) 2-naphthyl substituted at the 4, 5, 6, 7 and/or 8 positionswith 1 to 5 substituents selected from the group consisting alkyl,alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl, andheteroaryl,

[0143] (e) heteroaryl, and

[0144] (f) substituted heteroaryl containing 1 to 3 substituentsselected from the group consisting of alkyl, alkoxy, aryl, aryloxy,cyano, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided thatsaid substituents are not ortho to the heteroaryl attachment to the —NHgroup.

[0145] When m is zero, particularly preferred substituted phenyl R¹groups include mono-, di- and tri-substituted phenyl groups including3,5-disubstituted phenyls such as 3,5-dichlorophenyl,3,5-difluorophenyl, 3,5-di(trifluoromethyl)-phenyl, etc.;3,4-disubstituted phenyls such as 3,4-dichlorophenyl,3,4-difluorophenyl, 3-(trifluoromethyl)4-chlorophenyl,3-chloro4-cyanophenyl, 3-chloro4-iodophenyl, 3,4-methylenedioxyphenyl,etc.; 4-substituted phenyls such as 4-azidophenyl, 4-bromophenyl,4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl,4-iodophenyl, 4-(phenylcarbonyl)phenyl, 4-(1-ethoxy)ethylphenyl, etc.,3,4,5-trisubsituted phenyls such as 3,4,5-trifluorophenyl,3,4,5-trichlorophenyl, etc.

[0146] Specific R¹ groups for when m is zero include 3,4-dichlorophenyl,4-phenylfurazan-3-yl, and the like.

[0147] When m is zero, other preferred R¹ substituents include, by wayof example, 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl,benzothiazol-6-yl, 5-indolyl, phenyl, and the like.

[0148] When m is one, preferred R¹ groups include unsubstituted arylgroups such as phenyl, 1-naphthyl, 2-naphthyl, etc.; substituted arylgroups such as monosubstituted phenyls (preferably substituents at 3 or5 positions); disubstituted phenyls (preferably substituents at 3 and 5positions); and trisubstituted phenyls (preferably substituents at the3,4,5 positions). Preferably, the substituted phenyl groups do notinclude more than 3 substituents. Examples of substituted phenylsinclude, for instance, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl,2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl,4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl,4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl,4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl,3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl,3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl,2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl,3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,2-fluoro-3-trifluoromethylphenyl,

[0149] When m is one, other preferred R¹ groups include, by way ofexample, adamantyl, benzyl, 2-phenylethyl, 3-phenyl-n-propyl,4-phenyl-n-butyl, methyl, ethyl, n-propyl, iso-propyl, iso-butyl,sec-butyl, tell-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl,cyclobutyl, cyclohexyl, cyclopentyl, cyclopent-1-enyl, cyclopent-2-enyl,cyclohex-1-enyl, —CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclohexyl,—CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl,—CH2CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl, pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl),chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl,benzothiazol4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl,thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl,2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl,6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetraol-5-yl, allyl,2-(cyclohexyl)ethyl, (CH₃)₂CH═CHCH₂CH₂CH(CH₃)—, φC(O)CH₂—,thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl,2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, norboran-2-yl,(4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl,(3-methoxyphenyl)methyl, (3-hydroxyphenyl)methyl,(4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl,(4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,(2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl,(1-trifluoromethyl)ethyl, (4-methoxyphenyl)ethyl, CH₃OC(O)CH₂—,benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl,3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl),methoxymethyl, CH₃CH═CH—, CH₃CH₂CH═CH—, (4-chlorophenyl)C(O)CH₂—,(4-fluorophenyl)C(O)CH₂—, (4-methoxyphenyl)C(O)CH₂—,4-(fluorophenyl)—NHC(O)CH₂—, 1-phenyl-n-butyl, (φ)₂CHNHC(O)CH₂CH₂—,(CH₃)₂NC(O)CH₂—, (φ)₂CHNHC(O)CH₂CH₂—, methylcarbonylmethyl,(2,4-dimethylphenyl)C(O)CH₂—, 4-methoxyphenyl-C(O)CH₂—, phenyl-C(O)CH₂—,CH₃C(O)N(φ)—, ethenyl, methylthiomethyl, (CH₃)₃CNHC(O)CH₂—,4-fluorophenyl-C(O)CH₂—, diphenylmethyl, phenoxymethyl,3,4-methylenedioxyphenyl-CH₂—, benzo[b]thiophen-3-yl,(CH₃)₃COC(O)NHCH₂—, trans-styryl, H₂NC(O)CH₂CH₂—,2-trifluoromethylphenyl-C(O)CH₂, φC(O)NHCH(φ)CH₂—, mesityl,CH₃CH(═NHOH)CH₂—, 4—CH₃-φ-NHC(O)CH₂CH₂—, φC(O)CH(φ)CH₂—,(CH₃)₂CHC(O)NHCH(φ)—, CH₃CH₂OCH₂—, CH₃OC(O)CH(CH₃)(CH₂)₃—,2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH₃-benzofuran-3-yl,2-(2,4-dichlorophenoxy)ethyl, φSO₂CH₂—, 3-cyclohexyl-n-propyl,CF₃CH₂CH₂CH₂— and N-pyrrolidinyl.

[0150] Still other preferred R¹ groups include those set forth in theTables below.

[0151] When n is one or two, each R² is preferably (and independentlyfor n=2) selected from the group consisting of alkyl, substituted alkyl,alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.

[0152] Particularly preferred R² substituents include, by way ofexample, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, —CH₂CH(CH₂CH₃)₂, 2-methyl-n-butyl,6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl, cyclopentyl, cycloheptyl,allyl, iso-but-2-enyl, 3-methylpentyl, —CH₂-cyclopropyl,—CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclohexyl,—CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl, m-fluorophenyl,p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl,thiophen-2-yl, —CH₂—C(O)O-t-butyl, —CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂,-2-methylcyclopentyl, -cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃,—CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂, —CH₂CH═CHCH₃ (cis and trans), —CH₂OH,—CH(OH)CH₃, —CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH₂)₄NH-Boc, —(CH₂)₄NH₂,—CH₂-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl(2-pyridyl, 3-pyridyl and 4-pyridyl), —CH₂-naphthyl (e.g., 1-naphthyland 2-naphthyl), —CH₂-(N-morpholino), p-(N-morpholino-CH₂CH₂O)-benzyl,benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl,4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl, thien-3-yl, and the like.

[0153] Compounds of this invention include, by way of example,

[0154] 1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-aminodibenzosuberane

[0155]1-(R)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-(S)-indanol

[0156]1-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-(R)-indanol

[0157] 1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-indanol

[0158] 2-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1-cyclohexanol

[0159]1-(R,S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1,2,3,4-tetrahydro-2-naphthol

[0160]1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-aminobenz[f]cycloheptan-2-ol

[0161]5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol

[0162] 1-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-aminoindan-2-one

[0163] 2-(N′-(phenylacetyl)-L-alaninyl)aminocyclohexan-1-one

[0164]5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one

[0165]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-γ-butyrolactone

[0166] 3-(N′-(3,4-dichlorophenyl)-L-alaninyl)amino-γ-butyrolactone

[0167]4-(N′-(cyclopentylacetyl)-L-alaninyl)amino-1,1-dimethyl-3-isochromanone

[0168]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,1-dimethyl-3-isochromanone

[0169] 3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-γ-butyrolactam

[0170] 3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-δ-valerolactam

[0171]1-benzyl-3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-δ-valerolactam

[0172]3-N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-4-methyl-ε-caprolactam

[0173]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroquinolin-2-one

[0174]1-benzyl-3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroquinolin-2-one

[0175]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroisoquinolin-3-one

[0176]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0177]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0178]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0179]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-6-fluoro-1,2,3,4-tetrahydroisoquinolin-3-one

[0180]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-fluoro-1,2,3,4-tetrahydroisoquinolin-3-one

[0181]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0182]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0183]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-6-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0184]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0185](N′-(3,5-difluorophenylacetyl)-L-alaninyl)-(9-aminofluroren-1-yl)glycineδ-lactam

[0186] 3-(N′-(phenylacetyl)-L-alaninyl)amino-ε-caprolactam

[0187]3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-ε-caprolactam

[0188]3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-ε-caprolactam

[0189]3-(S)-N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(2-methoxyethyl)-ε-caprolactam

[0190]3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-ε-caprolactam

[0191]3-N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-ε-caprolactam

[0192]3-N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-ε-caprolactam

[0193]3-N′-(3,5-difluorophenylacetyl)-L-alaninyl-amino)-7-benzyl-ε-caprolactam

[0194]3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-4,7-methano-ε-caprolactam

[0195]3-(S)-(N′-(cyclopentylacetyl)-L-alaninyl)amino-1-benzyl-ε-caprolactam

[0196]3-(S)-(N′-(cyclopentylacetyl)-L-phenylglycinyl)amino-1-benzyl-ε-caprolactam

[0197]3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(2-phenethyl)-ε-caprolactam

[0198]3-(S)-(N′-(cyclopentylacetyl)-L-phenylglycinyl)amino-1-(2-phenethyl)-ε-caprolactam

[0199] 3-(N′-(3,4-dichlorophenyl)-D,L-alaninyl)amino-ε-caprolactam

[0200]3-(S)-(N′-(cyclopropylacetyl)-L-phenylglycinyl)amino-1-methyl-ε-caprolactam

[0201] 3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-8-octanelactam

[0202]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0203]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0204]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[0205]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

[0206]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

[0207]4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

[0208]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-1-methyl-2-indolinone

[0209]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril

[0210]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril

[0211]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-4-phenyl-3,4-trans-dihydrocarbostyril

[0212]1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

[0213]1-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-3-ethyl-4′-fluoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

[0214]3-(3,5-difluorophenylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0215]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0216]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

[0217]3-(N′-(cyclopentylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0218]3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0219]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0220]3-(3,5-difluorophenylacetyl)amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0221]3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0222]3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0223]3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0224]5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-6-one

[0225]5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one

[0226]5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one

[0227]1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

[0228]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[0229]5-(S)-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0230] 5-(S)-[N′-((S) and(R)-3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0231]5-(S)-[N′-(3,5-difluorophenyl-c-ketoacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0232]5-(S)-[N′-(3,5-difluorophenylacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0233]5-(S)-[N′-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0234]5-(S)-[N′-((S)-3,5-difluorophenyl-α-hydroxyacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0235]5-(S)-[N′-((S)-3,5-difluorophenyl-α-hydroxyacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0236]5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0237]5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(methylcarboxylate)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0238]5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(3,3-dimethyl-2-butanoyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0239]5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(morpholinylacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0240]5-(S)-(N′-((S)-(+)-2-Hydroxy-3-methylbutyryl)-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0241]5-[N′-cyclopentyl-α-hydroxyacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0242] 5-(S)-(N′-((S) and(R)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0243]5-[N′-cyclopentyl-α-hydroxyacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0244]5-[N′-cyclopentyl-α-hydroxyacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0245]5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one

[0246]5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0247]5-[N′-(2-hydroxy-3-methylbutyryl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0248] 5-(S)-[N′-((S andR)-2-hydroxy-3,3-dimethylbutyryl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0249]5-{N′-(⁴-phenyl-furazan-3-yl)alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0250]5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d]azepin-6-one

[0251]5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0252]5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0253]5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-(2′,2′,2′-trifluoroethyl)-5,7-dihydro-H-dibenz[b,d]azepin-6-one

[0254]5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0255]5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0256]5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0257]5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0258]5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0259]5-{N′-[(S)-3,5difluoromandelyl]-L-alaninyl}amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0260]5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0261]5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0262]5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0263]5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0264]5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0265]5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[0266]3-(N′-(3,4-methylenedioxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0267]3-(N′-(2-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0268]3-(N′-(⁴-isopropylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0269]3-(N′-(ethoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0270]3-(N′-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0271]3-(N′-(4-ethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0272]3-(N′-(2,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0273]3-(N′-(3,5-difluorobenzoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0274]3-(N′-(o-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0275]3-(N′-(3,3-diphenylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0276]3-(N′-(3-phenoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0277]3-(N′-(indole-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0278]3-(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0279]3-(N′-((4-methylphenoxy)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0280]3-(N′-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0281]3-(N′-(2-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0282]3-(N′-(3-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0283]3-(N′-(3,4-dichlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0284]3-(N′-(4-fluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0285]3-(N′-(methylthio)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0286]3-(N′-(methoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0287](S)-3-(N′-(phenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0288](S)-3-(N′-(phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0289](S)-3-(N′-(2-phenoxybutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0290](S)-3-(N′-(3-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0291](S)-3-(N′-(4-(trifluoromethyl)phenylacetyl)glycinyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0292](S)-3-(N′-(4-butoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0293](S)-3-(N′-(3-(2-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0294](S)-3-(N′-(4-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0295](S)-3-(N′-(isopropoxylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0296](S)-3-(N′-(1-phenyl-1H-tetrazole-5-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0297](S)-3-(N′-(3-(3,4-methylenedioxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0298](S)-3-(N′-(3-cyclopentylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0299](S)-3-(N′-(2-cyclopentene-1-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0300](S)-3-(N′-(2-chloro-6-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0301](S)-3-(N′-(cyclohexylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0302](S)-3-(N′-(2,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0303](S)-3-(N′-(pentafluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0304](S)-3-(N′-(3,5-dimethylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0305](S)-3-(N′-(4-chlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0306](S)-3-(N′-(3-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0307](S)-3-(N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0308](S)-3-(N′-(benzoylformyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0309](S)-3-(N′-(3,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0310](S)-3-(N′-(2,5-dimethylphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0311](S)-3-(N′-(2,6-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0312](S)-3-(N′-(2,4-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0313](S)-3-(N′-(mesitylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0314](S)-3-(N′-(4-biphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0315](S)-3-(N′-(3,4-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0316](S)-3-(N′-(trans-styrylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0317](S)-3-(N′-(3-benzoylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0318](S)-3-(N′-(trans-3-hexenoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0319](S)-3-(N′-(heptanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0320](S)-3-(N′-(3-(4-methylphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0321](S)-3-(N′-(3-(4-chlorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0322](S)-3-(N′-(3-phenylbutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0323](S)-3-(N′-(4-(4-methoxyphenyl)butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0324](S)-3-(N′-(3-methoxycarbonylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0325](S)-3-(N′-(4-phenylbutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0326](S)-3-(N′-(3-(benzylthio)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0327](S)-3-(N′-(3-methylpentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0328](S)-3-(N′-(6-methoxycarbonylheptanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0329](S)-3-(N′-(2-indanylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0330](S)-3-(N′-(4-methoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0331](S)-3-(N′-(2-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0332](S)-3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0333](S)-3-(N′-(3-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-L,4-benzodiazepin-2-one

[0334](S)-3-(N′-(4-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0335](S)-3-(N′-(2,6-difluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0336](S)-3-(N′-(-(4-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0337](S)-3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0338](S)-3-(N′-(m-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0339](S)-3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0340](S)-3-(N′-(4-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0341](S)-3-(N′-(2-naphthylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0342](S)-3-(N′-(3-chlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0343](S)-3-(N′-(3-methylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0344](S)-3-(N′-(3,4-methylenedioxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0345](S)-3-(N′-(2-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0346](S)-3-(N′-(4-isopropylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0347](S)-3-(N′-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0348](S)-3-(N′-(phenylmercaptoacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0349](S)-3-(N′-(4-ethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0350](S)-3-(N′-(2,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0351](S)-3-(N′-(o-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0352](S)-3-(N′-(3,3-diphenylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0353](S)-3-(N′-(3-phenoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0354](S)-3-(N′-(indole-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0355](S)-3-(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0356](S)-3-(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0357](S)-3-(N′-(2-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-l1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0358](S)-3-(N′-(3-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0359](S)-3-(N′-(4-fluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0360](S)-3-(N′-(2,4-dichlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0361] (S)-3-(N′-((methylthio)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0362](S)-3-(N′-(4-fluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0363](S)-3-(N′-(4-thionaphthenacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0364] (S)-3-(N′-(methoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-H-1,4-benzodiazepin-2-one

[0365](S)-3-(N′-(ethoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0366](S)-3-(N′-(3-indolepropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0367](S)-3-(N′-(3-(2-chlorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0368](S)-3-(N′-(butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0369](S)-3-(N′-(hexanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0370](S)-3-(N′-(5-phenylpentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0371](S)-3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0372](S)-3-(N′-(4-nitrophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0373](S)-3-(N′-(3-(3-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0374](S)-3-(N′-(5-methylhexanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0375](S)-3-(N′-(hydrocinnamyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0376](S)-3-(N′-(octanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0377](S)-3-(N′-(3-(3-hydroxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0378](S)-3-(N′-(3-(4-hydroxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0379](S)-3-(N′-(3,4,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0380](S)-3-(N′-(5-hydantoinacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0381](S)-3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0382](S)-3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0383](S)-3-(N′-(2-methyl-3-Benzofuranacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0384](S)-3-(N′-(propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0385](S)-3-(N′-(cyclopropylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0386](S)-3-(N′-(3-methoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0387](S)-3-(N′-(5-(thienyl)pentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0388](S)-3-(N′-(3-(4-fluorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0389](S)-3-(N′-(3-(4-fluorophenoxy)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4benzodiazepin-2-one

[0390](S)-3-(N′-(2-norbornaneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0391](S)-3-(N′-(2,3-difluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0392](S)-3-(N′-(3-pentenoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0393](S)-3-(N′-(4-(2,4-dichlorophenoxy)butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0394](S)-3-(N′-(2,3-dichlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0395](S)-3-(N′-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0396](S)-3-(N′-(2-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0397] (S)-3-(N′-(2-(4-cyanophenoxy)-2-methylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0398](S)-3-(N′-(2-nitrophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0399](S)-3-(N′-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0400](S)-3-(N′-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0401](S)-3-(N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0402](S)-3-(N′-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0403](S)-3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0404](S)-3-(N′-(2-fluoro4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0405](S)-3-(N′-(4-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0406](S)-3-(N′-(3-(4-fluorobenzoyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0407](S)-3-(N′-((2-methylphenoxy)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0408](S)-3-(N′-(4-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0409](S)-3-(N′-(3-(phenylsulfonyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0410](S)-3-(N′-(2-methoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0411](S)-3-(N′-(2-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0412](S)-3-(N′-(p-isopropylphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0413](S)-3-(N′-(4-pentenoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0414](S)-3-(N′-(4-hydroxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0415](S)-3-(N′-(4-oxopentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0416](S)-3-(N′-(2-hydroxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0417](S)-3-(N′-(3,4-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0418](S)-3-(N′-(3-(4-methoxybenzoyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0419](S)-3-(N′-(thien-3-ylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0420](S)-3-(N′-(6-phenylhexanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0421](S)-3-(N′-(isovaleryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0422](S)-3-(N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0423](S)-3-(N′-(2,4,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0424](S)-3-(N′-(1-adamantaneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0425](S)-3-(N′-(cyclohexanepentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0426](S)-3-(N′-(2-thiopheneacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0427](S)-3-(N′-(3-(trifluoromethyl)phenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0428](S)-3-(N′-(3,5-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0429](S)-3-(N′-(3-tolylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0430](S)-3-(N′-(3-fluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0431](S)-3-(N′-(3-bromophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0432](S)-3-(N′-(3-chlorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0433](S)-3-(N′-(3,4-methylenedioxyphenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0434](S)-3-(N′-(phenylmercaptoacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0435](S)-3-(N′-(acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0436](S)-3-(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0437](S)-3-(N′-((methylthio)acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0438](S)-3-(N′-(phenoxyacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0439](S)-3-(N′-(phenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0440](S)-3-(N′-(cyclohexylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0441](S)-3-(N′-(2,5-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0442](S)-3-(N′-(benzo[b]thiophene-3-acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0443](S)-3-(N′-(benzoylformyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0444](S)-3-(N′-(2,6-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0445](S)-3-(N′-(2,4-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0446](S)-3-(N′-(3,4-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0447](S)-3-(N′-(butyryl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0448](S)-3-(N′-(heptanoyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0449](S)-3-(N′-(4-(2-thienyl)butyryl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0450](S)-3-(N′-(5-methylhexanoyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0451](S)-3-(N′-(hydrocinnamyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0452](S)-3-(N′-(cyclopentylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0453](S)-3-(N′-(propionyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0454](S)-3-(N′-(3,4,5-trifluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0455](S)-3-(N′-(4-phenylbutyryl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0456]3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0457]3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0458]3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0459]3-(N′-(²-thiopheneacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0460]3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0461]3-(N′-(²-thiopheneacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0462]3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0463]3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0464]3-(N′-(2-thiopheneacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0465]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0466]3-(N′-(3,5difluorophenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0467]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0468]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0469]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0470]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0471]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0472]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0473]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0474]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0475]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0476]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0477]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0478]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0479]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0480]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0481]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0482]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0483]3-(N′-(methylthio)acetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0484]3-(N′-(methylthio)acetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0485]3-(N′-(methylthio)acetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0486]3-(N′-(methylthio)acetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0487]3-(N′-(methylthio)acetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0488]3-(N′-(methylthio)acetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0489]3-(N.′-(methylthio)acetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0490]3-(N′-(methylthio)acetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0491]3-(N′-(methylthio)acetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0492]3-(N′-(phenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0493]3-(N′-(phenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0494]3-(N′-(phenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0495]3-(N′-(phenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0496]3-(N′-(phenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0497]3-(N′-(phenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0498]3-(N′-(phenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0499]3-(N′-(phenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0500]3-(N′-(phenylacetyl)-L-alaninyl)-amino-)2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0501]3-(N′-(benzoylformyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0502]3-(N′-(benzoylformyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0503]3-(N′-(benzoylformyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0504]3-(N′-(benzoylformyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0505]3-(N′-(benzoylformyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0506]3-(N′-(benzoylformyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0507]3-(N′-(benzoylformyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0508]3-(N′-(benzoylformyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0509]3-(N′-(benzoylformyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0510]3-(N′-(butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0511]3-(N′-(butyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5phenyl-1H-1,4-benzodiazepin-2-one

[0512]3-(N′-(butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0513]3-(N′-(butyryl)-L-alaninyl)amino-7chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0514]3-(N′-(butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0515]3-(N′-(butyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0516]3-(N′-(butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0517]3-(N′-(butyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0518]3-(N′-(butyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0519]3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0520]3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0521]3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0522]3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-H-1,4-benzodiazepin-2-one

[0523]3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0524]3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0525]3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0526]3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0527]3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0528]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0529]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0530] 3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-l-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0531]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0532]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0533]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0534]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0535]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0536]3-(N′-(cyclopentylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0537]3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0538]3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0539]3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0540]3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0541]3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0542]3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0543]3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0544]3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0545]3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)-amino-)2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0546]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0547] 3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino--(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0548]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0549]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0550]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0551]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0552]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0553]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0554]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0555]3-(N′-(isovaleryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0556]3-(N′-(isovaleryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0557]3-(N′-(isovaleryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0558]3-(N′-(isovaleryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0559]3-(N′-(isovaleryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0560]3-(N′-(isovaleryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0561]3-(N′-(isovaleryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0562]3-(N′-(isovaleryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0563]3-(N′-(isovaleryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0564]3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0565]3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0566]3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0567]3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0568]3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0569]3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0570]3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0571]3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0572]3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0573]3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one

[0574]3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0575]3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one

[0576]3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0577]3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0578]3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0579]3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0580]3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0581]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-fluorobenzyl)-1H-1,4-benzodiazepin-2-one

[0582]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-one

[0583]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one

[0584]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one

[0585]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one

[0586]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one

[0587]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-ethylbutyl)-1H-1,4-benzodiazepin-2-one

[0588]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one

[0589]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-phenylethyl)-1H-1,4-benzodiazepin-2-one

[0590]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one

[0591]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-(N-phthalimnidyl)ethyl)-1H-1,4-benzodiazepin-2-one

[0592]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-biphenylmethyl)-1H-l,4-benzodiazepin-2-one

[0593]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-((2-tetrahydrofuranyl)methyl)-1H-1,4-benzodiazepin-2-one

[0594]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-(1,4-benzodioxanyl)methyl)-1H-1,4-benzodiazepin-2-one

[0595]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one

[0596]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethyl-2-oxo-propyl)-1H-1,4-benzodiazepin-2-one

[0597]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one

[0598]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one

[0599]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one

[0600]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-one

[0601]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-ethyl-1H-1,4-benzodiazepin-2-one

[0602]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-pyridylmethyl)-1H-1,4-benzodiazepin-2-one

[0603]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-oxo-2-(N-indolinyl)ethyl)-1H-1,4-benzodiazepin-2-one

[0604]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one

[0605]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one

[0606]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-one

[0607]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one

[0608]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one

[0609]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one

[0610]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(isopropyl)-1H-1,4-benzodiazepin-2-one

[0611]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one

[0612]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-ethylbutyl)-1H-1,4-benzodiazepin-2-one

[0613]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one

[0614]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-phenylethyl)-1H-1,4-benzodiazepin-2-one

[0615]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one

[0616]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-(N-phthalimidyl)ethyl)-1H-1,4-benzodiazepin-2-one

[0617]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-biphenylmethyl)-1H-1,4-benzodiazepin-2-one

[0618]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one

[0619]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethyl-2-oxo-butyl)-1H-1,4-benzodiazepin-2-one

[0620]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one

[0621]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one

[0622]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one

[0623]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclopropylmethyl)-1H-1,4-benzodiazepin-2-one

[0624]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-one

[0625]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-ethyl-1H-1,4-benzodiazepin-2-one

[0626]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one

[0627]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-propyl-1H-1,4-benzodiazepin-2-one

[0628]3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one

[0629]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-one

[0630]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one

[0631]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one

[0632]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one

[0633]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-(isopropyl)-1H-1,4-benzodiazepin-2-one

[0634]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one

[0635]3-(N′-(4,4,⁴-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-ethylbutyl)-1H-1,4-benzodiazepin-2-one

[0636]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one

[0637]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one

[0638]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-biphenylmethyl)-1H-1,4-benzodiazepin-2-one

[0639]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one

[0640]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethyl-2-oxo-butyl)-1H-1,4-benzodiazepin-2-one

[0641]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one

[0642]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one

[0643]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one

[0644]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclopropylmethyl)-1H-1,4-benzodiazepin-2-one

[0645]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-one

[0646]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(ethyl)-1H-1,4-benzodiazepin-2-one

[0647]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one

[0648]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(propyl)-1H-1,4-benzodiazepin-2-one

[0649]3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one

[0650]3-(N′-(L-(+)-mandelyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0651](S)-3-(N′-(N-pyrrolidinylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0652]3-(N′-(2-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0653]3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0654]3-(N′-(3-(trifluoromethyl)phenylacetic)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0655]3-(N′-(4-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0656]3-(N′-(3-(4-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0657]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0658]3-(N′-(m-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0659]3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0660]3-(N′-(3-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0661]3-(N′-(4-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0662]3-(N′-(2-naphthylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0663]3-(N′-(3-methylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0664]3-[(N′-(4-methoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0665]3-[(N′-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0666]3-[(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0667]3-[(N′-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0668]3-[(N′-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0669]3-[(N′-(4-ethoxyphenylacetyl)-L-alaninyl)amino]l-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0670]3-[(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0671]3-[(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0672]3-[(N′-((methylthio)acetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0673]3-[(N′-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0674]3-[(N′-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0675]3-[(N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0676]3-[(N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0677]3-[(N′-(4-biphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0678]3-[(N′-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0679]3-[(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0680]3-[(N′-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0681]3-[(N′-(3-methoxycarbonylpropionyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0682] 3-[(N′-(2,6-difluoromandelyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0683]3-[(N′-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0684]3-[(N′-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0685]3-[(N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0686]3-[(N′-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0687]3-[(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0688]3-[(N′-(4-isopropylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0689]3-[(N′-(beta-phenyl]actyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0690]3-[(N′-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0691]3-[(N′-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0692]3-[(N′-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0693]3-[(N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0694]3-[(N′-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0695]3-[(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0696]3-[(N′-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0697]3-[(N′-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0698]3-[(N′-(4-methocyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0699]3-[(N′-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0700]3-[(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0701]3-[(N′-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0702]3-[(N′-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0703]3-[(N′-(4-ethoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0704]3-[(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0705]3-[(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0706]3-[(N′-((methylthio)acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0707]3-[(N′-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0708]3-[(N′-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0709]3-[(N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0710]3-[(N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0711]3-[(N′-(4-biphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0712]3-[(N′-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0713]3-[(N′-(4-(2-thienyl)butyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0714]3-[(N′-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0715]3-[(N′-(2,6-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0716]3-[(N′-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0717]3-[(N′-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0718]3-[(N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0719]3-[(N′-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0720]3-[(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0721]3-[(N′-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0722]3-[(N′-(beta-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0723]3-[(N′-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0724]3-[(N′-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0725]3-[(N′-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0726]3-[(N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0727]3-[(N′-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0728]3-[(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0729]3-[(N′-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0730]3-[(N′-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0731]3-[(N′-(4-methoxyphenylacetyl)-L-alaninyl]amino3-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0732]3-[(N′-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0733]3-[(N′-(N″-acetyl-N″-phenylglycinyl)L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0734]3-[(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0735]3-[(N′-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0736]3-[(N′-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0737]3-[(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0738]3-[(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0739]3-[(N′-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0740]3-[(N′-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0741]3-[(N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0742]3-[(N′-(benzoylformyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0743]3-[(N′-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0744]3-[(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0745]3-[(N′-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0746]3-[(N′-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0747]3-[(N′-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0748]3-[(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-5diethyl aminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0749]3-[(N′-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0750]3-[(N′-(beta-phenyl]actyl)-L-alaninyl)amino3-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0751] 3-[(N′-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0752]3-[(N′-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0753]3-[(N′-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0754]3-[(N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0755]3-[(N′-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0756]3-[(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0757]3-[(N′-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0758]3-[(N′-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0759]3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0760]3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0761]3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0762]3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0763]3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0764]3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0765]3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0766]3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0767]3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0768]3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0769]3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0770]3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0771]3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0772]3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0773]3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0774]3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0775]3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0776]3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0777]3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0778]3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0779]3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0780]3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0781]3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0782]3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0783]3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0784]3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0785]3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0786]3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0787]3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-l,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0788]3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0789]3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0790]3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0791]3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0792]3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0793]3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0794]3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0795]3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0796]3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0797]3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0798]3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0799]3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0800]3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0801]3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0802]3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0803]3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0804]3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0805]3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0806]3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0807]3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0808]3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0809]3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0810]3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0811]3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0812]3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0813]3-[N-(cyclopentylacetyl)-L-serinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0814]3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0815]3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0816]3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0817]3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0818]3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0819]3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0820]3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0821]3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0822]3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0823]3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-.tetrahydro-1H-1,5-benzodiazepine

[0824]3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0825]3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0826]3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0827]3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0828]3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0829]3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0830]3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0831]3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0832]3-[N-(4,4,4-trifluorobutryl)-L-phenytalaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0833]3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0834]3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0835]3-[N-(4,4,4-trifluorobutryl)-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0836]3-[N-(4,4,4-trifluorobutryl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0837]3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0838]3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0839]3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0840]3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0841]3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0842]3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0843]3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0844]3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0845]3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0846]3-[N-(4,4,4-trifluorobutryl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0847]3-[N-(4,4,4-trifluorobutryl)-threoninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0848]3-[N-(4,4,4-trifluorobutryl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0849]3-(3,5-difluorophenylacetyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0850]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0851]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0852]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(1-piperidinyl)-1H-1,4-benzodiazepin-2-one

[0853]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0854]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[0855]3-[N′-(3,5-difluorophenylacetyl)-N′-methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0856]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one

[0857]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[0858]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

[0859]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[0860]3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-valinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0861]3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0862]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[0863]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[0864]3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0865]3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-valinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0866]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepin-2-one

[0867]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-isobutyl-5-phenyl)-1H-1,4-benzodiazepin-2-one

[0868]3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0869]3-[N′-(3,5-difluorophenyl-α-oxoacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0870]3-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0871]3-[N′-(3,5-difluorophenylacetyl)-L-valinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0872]3-[N′-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0873]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0874]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-cyclopropylmethyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0875]3-[N′-(3,5-difluorophenyl-α-fluoroacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0876]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-n-propyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0877] 3-[N′-(3-methylbutyryl)-L-phenylglycinyl]amino-2,3-dihydro-l-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0878]3-[N′-(3,5-difluorophenylacetyl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0879]3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0880]3-[N′-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0881]3-[N′-(2-phenylthioacetyl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0882]3-[N′-(3-(4-methoxyphenyl)propionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0883]3-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0884]3-[N′-(4-cyclohexylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0885]3-[N′-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0886]3-[N′-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0887]3-[N′-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0888]3-[N′-(3,3-dimethylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[0889]3-[N′-(thien-2-yl-acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0890]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0891]3-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0892]3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0893]3-[N′-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0894]3-[N′-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0895]3-[N′-(3,5-di(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0896]3-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0897]3-[N′-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0898]3-[N′-(2,3,4,5,6-pentafluorophenoxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0899]3-[N′-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0900]3-[N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0901]3-[N′-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0902]3-[N′-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0903]3-[N′-(4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0904]3-[N′-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0905]3-[N′-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0906]3-[N′-(2,6-difluorophenyl)-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0907]3-[N′-(4-fluorophenyl)-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0908]3-[N′-(2,5-difluorophenyl)-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0909]3-[N′-(2,4,6-trifluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0910]3-[N′-(2-trifluoromethyl4-fluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0911]3-[N′-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0912]3-[N′-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0913]3-[N′-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0914]3-[N′-(phenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0915]3-[N′-(4-chlorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0916]3-[N′-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0917]3-[N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0918]3-[N′-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0919]3-[N′-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0920]3-[N′-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0921]3-[N′-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0922]3-[N′-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0923]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0924]3-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0925]3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0926]3-[N′-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0927]3-[N′-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0928]3-[N′-(3,5-di-(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0929]3-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0930]3-[N′-(2-cyclomethylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0931]3-[N′-(2,3,4,5,6-pentafluorophenoxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0932]3-[N′-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0933]3-[N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0934]3-[N′-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0935]3-[N′-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0936]3-[N′-(4-(2-thienyl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0937]3-[N′-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0938]3-[N′-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0939]3-[N′-(2,6-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0940]3-[N′-(4-fluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0941]3-[N′-(2,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0942]3-[N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0943]3-[N′-(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0944]3-[N′-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0945]3-[N′-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0946]3-[N′-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0947]3-[N′-(phenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0948]3-[N′-(4-chlorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0949]3-[N′-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0950]3-[N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(ter-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0951]3-[N′-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0952]3-[N′-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0953]3-[N′-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0954]3-[N′-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0955]3-[N′-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0956]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0957]3-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0958]3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0959]3-[N′-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0960]3-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0961]3-[N′-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0962]3-[N′-(2,3,4,5,6-pentafluorophenoxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0963]3-[N′-(2-thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0964]3-[N′-(2-phenyl-2-oxoacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0965]3-[N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0966]3-[N′-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0967]3-[N′-((3,4-difluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0968]3-[N′-((4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0969]3-[N′-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0970]3-[N′-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0971]3-[N′-(2,6-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0972]3-[N′-(4fluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0973]3-[N′-(2,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0974]3-[N′-(4-hydroxymethylphenoxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0975]3-[N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0976]3-[N′-(2-trifluoromethyl4-fluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0977]3-[N′-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0978]3-[N′-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0979]3-[N′-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0980]3-[N′-(phenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0981]3-[N′-(4-chlorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[0982]3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-3-thienylglycinyl]amino-2,4-dioxo-1,5-bis(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0983]3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0984]3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2-oxo-1-methyl-5-phenyl-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0985]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amini-L-1H-imidazole[1,2-a]-6-phenyl-1,4-benzodiazepine

[0986]4-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-L-1H-imidazole[1,2-a]-2,4-dihydro-6-phenyl-1,4-benzodiazepine

[0987]4-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-L-4H[1,2,4]triazole[4,3-a]-6-phenyl-1,4-benzodiazepine

[0988]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0989]3-[N′-(3,5-difluorophenylacetyl)-(R)-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0990]3-[N′-(cyclopropylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0991]3-[N′-(cyclopentylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0992]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0993]3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0994]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0995]3-[N′-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0996]3-[N′-(cyclopropylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0997]3-[N′-(3,5-difluorophenylacetyl)-5-2-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0998]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0999]3-[N′-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[1000]3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[1001]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[1002]3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[1003]3-[N′-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[1004]3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[1005]3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[1006]3-[N′-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[1007]3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[1008]3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[1009]5-{N′-(cyclopentylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1010]5-{N′-(3-cyclopentylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1011]5-{N′-(cyclohexylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1012]5-{N′-(t-butylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1013]5-{N′-(phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1014]5-{N′-(3-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1015]5-{N′-(3-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1016]5-{N′-(3-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1017]5-{N′-(3-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1018]5-{N′-(4-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1019]5-{N′-(hexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1020]5-{N′-(heptanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1021]5-{3,4-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1022]5-{N′-(cyclopropylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1023]5-{N′-(2-cyclopentene-1-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1024]5-{N′-(3-cyclohexylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1025]5-{N′-(isovaleryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1026]5-{N′-(citronellyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1027]5-{N′-(3-benzoylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1028]5-{N′-(2-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1029]5-{N′-(4-pentenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1030]5-{N′-(valeryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1031]5-{N′-(2-thiophenecetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1032]5-{N′-(4-(2-thienyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1033]5-{N′-(4-(4-nitrophenyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1034]5-{N′-(2,4-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1035]5-{N′-(2,6-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1036]5-{N′-(4-isopropylphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1037]5-{N′-(1-adamantaneacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1038]5-{N′-(5-cyclohexanepentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1039]5-{N′-((methylthio)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1040]5-{N′-(2-thiophenepentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1041]5-{N′-(2-norbornaneacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1042]5-{N′-(3,5-difluorophenylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1043]5-{N′-(3,5-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1044]5-{N′-(3,5-difluorophenylacetyl)-3-cyclopropylalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1045]5-{N′-(3,5-difluorophenylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1046]5-{N′-(3,5-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1047]5-{N′-(3,5-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1048]5-{N′-(cyclohexylacetyl)4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1049]5-{N′-(cyclopropylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1050]5-{N′-(isovaleryl)4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1051]5-{N′-(3-(trifluoromethyl)phenylacetyl)4ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1052]5-{N′-(3,4-difluorophenylacetyl)4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1053]5-{N′-(2,4-difluorophenylacetyl)4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1054]5-{N′-(3-fluorophenylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1055]5-{N′-(cyclopentylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1056]5-{N′-(cyclohexylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1057]5-{N′-(cyclopropylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1058]5-{N′-(2-thiopheneacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1059]5-{N′-(isovaleryl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1060]5-{N′-(3-(trifluoromethyl)phenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1061]5-{N′-(4-fluorophenylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-5dihydro-6H-dibenz[b,d]azepin-6-one

[1062]5-{N′-(3,4-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1063]5-{N′-(2,4-difluorophenylacetyl)4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1064]5-{N′-(3-fluorophenylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1065]5-{N′-(cyclopentylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1066]5-{N′-(cyclohexylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1067]5-{N′-(cyclopropylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1068]5-{N′-(isovaleryl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1069]5-{N′-(4-fluorophenylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1070]5-{N′-(3,4-difluorophenylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1071]5-{N′-(2,4-difluorophenylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7dihydro-6H-dibenz[b,d]azepin-6-one

[1072]5-{N′-(3-fluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1073]5-{N′-(cyclopentylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1074]5-{N′-(cyclohexylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1075]5-{N′-(cyclopropylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1076]5-{N′-(isovaleryl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1077]5-{N′-(3-(trifluoromethyl)phenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1078]5-{N′-(4-fluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1079]5-{N′-(3,4-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1080]5-{N′-(2,4-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1081]5-{N′-(4-methoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1082]5-{N′-(3-(4-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1083]5-{N′-(1-naphthylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1084]5-{N′-(3,4-methylenedioxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1085]5-{N′-(hydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1086]5-{N′-(octanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1087]5-{N′-(3-(3-hydroxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1088]5-{N′-(3-(4-methylphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1089]5-{N′-(3-(4-chlorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1090]5-{N′-(3-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1091]5-{N′-(3-(4-hydroxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1092]5-{N′-(3,4,5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1093]5-{N′-(4-(4-methoxyphenyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1094]5-{N′-(3-(methoxycarbonyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1095]5-{N′-(4-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1096]5-{N′-(3-(benzylthio)-propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1097]5-{N′-(3-methylpentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1098]5-{N′-(7-carbomethoxyheptanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1099]5-{N′-(2-indanylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1100]5-{N′-(5-carbomethoxypentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1101]5-{N′-(2-methyl-3-Benzofuranacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1102]5-{N′-(propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1103]5-{N′-(3-methoxypropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1104]5-{N′-(3-(4-fluorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1105]5-{N′-(3-(4-fluorophenoxy)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1106]5-{N′-(3-pentenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1107]5-{N′-(4-(2,4-dichlorophenoxy)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1108]5-{N′-(2,3-dichlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1109]5-{N′-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1110]5-{N′-(4′-fluorosuccinanilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1111]5-{N′-(N-(diphenylmethyl)glutaramyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1112]5-{N′-(2-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1113]5-{N′-(cyanoacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1114]5-{N′-(succinanilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1115]5-{N′-(2,4-dichlorophenoxyaceyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1116]5-{N′-(2-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1117]5-{N′-(beta-propylhydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1118]5-{N′-(3-(2,4-dimethylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1119]5-{N′-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1120]5-{N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1121]5-{N′-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1122]5-{N′-(2-fluoro-4-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1123]5-{N′-(4-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1124]5-{N′-(4-methoxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1125]5-{N′-(2-methoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1126]5-{N′-(2-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1127]5-{N′-(4-benzyloxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1128]5-{(N′-(4-hydroxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1129]5-{N′-(levulinyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1130]5-{N′-(2-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1131]5-{N′-(3,4-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1132]5-{N′-(3-(4-methoxybenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1133]5-{N′-(3-(4-phenylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1134]5-{N′-(3-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1135]5-{N′-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1136]5-{N′-(thiophene-3-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1137]5-{N′-(6-phenylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1138]5-{N′-(4-cyclohexanebutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1139]5-{N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1140]5-{N′-(2,4,5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1141]5-{N′-(vinylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1142]5-{N′-(3-methylthiopropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1143]5-{N′-(3-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1144]5-{N′-(N-tert-butylsuccinamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1145]5-{N′-(4-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1146]5-{N′-(3-(4-fluorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1147]5-{N′-(o-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1148]5-{N′-(p-tolylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1149]5-{N′-(m-tolylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1150]5-{N′-(3,4-dichlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1151]5-{N′-(4-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1152]5-{N′-(3-methylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1153]5-{N′-(4-isopropylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1154]5-{N′-(4-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1155]5-{N′-(phenylmercaptoacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1156]5-{N′-(4-ethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1157]5-{N′-(2,5-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1158]5-{N′-(o-tolylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1159]5-{N′-(3,3-diphenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1160]5-{N′-(3-phenoxypropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1161]5-{N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1162]5-{N′-((4-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1163]5-{N′-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1164]5-{N′-(3-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1165]5-{N′-(3,4-dichlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1166]5-{N′-(4-fluorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1167]5-{N′-(3,4,5-trimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1168]5-{N′-(2,4-dichlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1169]5-{N′-(4-thianaphthenacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1170]5-{N′-(methoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1171]5-{N′-(ethoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1172]5-{N′-(phenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1173]5-{N′-(3-methoxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1174]5-{N′-(4-butoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1175]5-{N′-(3-(2-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1176]5-{N′-(N,N-dimethylsuccinamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1177]5-{N′-(3-(3,4-methylenedioxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1178]5-{N′-(2-chloro-6-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1179]5-{N′-(2,5-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1180]5-{N′-(2,3,4,5,6-pentafluorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1181]5-{N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1182]5-{N′-(3,5-dimethylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1183]5-{N′-(4-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1184]5-{N′-(3-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1185]5-{N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1186]5-{N′-(3,5-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1187]5-{N′-(2,5-dimethylphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1188]5-{N′-(mesitylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1189]5-{N′-(4-biphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1190]5-{N′-(N-(tert-butoxycarbonyl)-3-aminopropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1191]5-{N′-(trans-styrylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1192]5-{N′-(4-acetamidobutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1193]5-{N′-(3-(2-chlorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1194]5-{N′-(butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1195]5-{N′-(trans-3-hexenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1196]5-{N′-(5-phenylvaleryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1197]5-{N′-(3-(3-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1198]5-{N′-(4-chloro-beta-methylhydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1199]5-{N′-(3-(trifluoromethyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7,-dihydro-6H-dibenz[b,d]azepin-6-one

[1200]5-{N′-(alpha-naphthoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1201]5-{N′-(3-(4-phenoxybenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1202]5-{N′-(3-(2-trifluoromethylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1203]5-{N′-(3-benzoylamino-3-phenyl-propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1204]5-{N′-(4-(hydroxyimino)pentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1205]5-{N′-(4′-methylglutaranilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1206]5-{N′-((4-(4-ethyl-phenoxy)-phenoxy)-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1207]5-{N′-(3-benzoyl-3-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1208]5-{N′-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1209]5-{N′-(4,4,4-trifluorobutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1210]5-{N′-(3-isobutyrylamino-3-phenyl-propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1211]5-{N′-((2-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1212]5-{N′-(3-(phenylsulfonyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1213]5-{N′-(4-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1214]5-{N′-(3-ethoxypropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1215]5-{N′-(2,3-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1216]5-{N′-(2,6-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-fluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1217]5-{N′-(2,5-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1218]5-{N′-(beta-phenyllactyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1219]5-{N′-(mandelyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1220]5-{N′-(p-chloromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1221]5-{N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1222]5-{N′-(4-bromomandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1223]5-{N′-(L-(+)-lactyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1224]5-{N′-(D-3-phenyllactyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1225]5-{N′-(5-methylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1226]5-{N′-(3,5-difluorophenylacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1227]5-{N′-(3,5-difluorophenylacetyl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1228]5-{N′-(3,5-difluorophenylacetyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1229]5-{N′-(3,5-difluorophenylacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1230]5-{N′-(3,5-difluorophenylacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1231]5-{N′-(3,5-difluorophenylacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1232]5-{N′-(2-thiopheneacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1233]5-{N′-(2-thiopheneacetyl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1234]5-{N′-(2-thiopheneacetyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepih-6-one

[1235]5-{N′-(2-thiopheneacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1236]5-{N′-(2-thiopheneacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1237]5-{N′-(2-thiopheneacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1238]5-{N′-(isovaleryl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1239]5-{N′-(isovaleryl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1240]5-{N′-(isovaleryl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1241]5-{N′-(isovaleryl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1242]5-{N′-(isovaleryl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1243]5-{N′-(isovaleryl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1244]5-{N′-(phenylacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1245]5-{N′-(phenylacetyl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1246]5-{N′-(phenylacetyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1247]5-{N′-(phenylacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1248]5-{N′-(phenylacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[1249]5-{N′-(phenylacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onePreferred cyclic groups defined by W and —C(H)_(p)C(═X)— includecycloalkyl, lactone, lactam, benzazepinone, dibenzazepinone andbenzodiazepine groups. In one preferred embodiment, the cyclic groupdefined by W and —C(H)_(p)C(═X)—, forms a cycloalkyl group of theformula:

[1250] wherein T is selected from the group consisting of alkylene andsubstituted alkylene.

[1251] A preferred cycloalkyl group is represented by the formula:

[1252] wherein each V is independently selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is aninteger from 0 to 4; and w is an integer from 0 to 3.

[1253] Preferably t is an integer from 0 to 2 and, more preferably, isan integer equal to 0 or 1.

[1254] In another preferred embodiment, the cyclic group defined by W,together with —C(H)_(p)C(═X)— is a ring of the formula:

[1255] wherein p is zero or one, T is selected from the group consistingof alkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

[1256] Particularly preferred alcohol or thiol substituted groupsinclude

[1257] wherein each V is independently selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is aninteger from 0 to 4; and w is an integer from 0 to 3.

[1258] Preferably t is an integer from 0 to 2 and, more preferably, isan integer equal to 0 or 1.

[1259] Yet another preferred embodiment of the cyclic group defined byW, together with —C(H)_(p)C(═X)—, is a ring of the formula:

[1260] wherein p is zero or one, T is selected from the group consistingof alkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

[1261] Particularly preferred cyclic ketone and thioketone groupsinclude:

[1262] wherein each V is independently selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is aninteger from 0 to 4; and w is an integer from 0 to 3.

[1263] Preferably t is an integer from 0 to 2 and, more preferably, isan integer equal to 0 or 1.

[1264] In another preferred embodiment, the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

[1265] wherein p is zero or one, T is selected from the group consistingof alkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

[1266] Particularly preferred lactone and thiolactone groups include:

[1267] wherein each V is independently selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alky, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; t is aninteger from 0 to 4; and w is an integer from 0 to 3.

[1268] Preferably t is an integer from 0 to 2 and, more preferably, isan integer equal to 0 or 1.

[1269] In another preferred embodiment, the cyclic group defined by Wand —C(H)_(p)C(═X)—, forms a lactam ring of the formula:

[1270] or a thiolactam ring of the formula:

[1271] wherein p is zero or one, T is selected from the group consistingof alkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, h-eteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

[1272] Particularly preferred lactam and thiolactam groups include:

[1273] wherein A-B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene and —N═CH—; Q′is oxygen or sulfur; each V is independently selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; R^(b) isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl,aryl, heteroaryl, heterocyclic, and the like; R^(c) is selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, substitutedalkenyl, aryl, heteroaryl, heterocyclic, cycloalkyl, and substitutedcycloalkyl; t is an integer from 0 to 4; t′ is an integer from 0 to 3;and w is an integer from 0 to 3.

[1274] Preferably t is an integer from 0 to 2 and, more preferably, isan integer equal to 0 or 1.

[1275] In another preferred embodiment, the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

[1276] wherein p is zero or one, T is selected from the group consistingof alkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of -O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

[1277] A still further preferred embodiment is directed to a ring groupdefined by W, together with —C(H)_(p)C(═X)—, of the formula:

[1278] wherein p is zero or one, T is selected from the group consistingof alkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to 3.

[1279] This invention also provides for novel pharmaceuticalcompositions comprising a pharmaceutically inert carrier and a compoundof the formula I above.

[1280] Still further, this invention provides for novel compounds of theformula

[1281] wherein R¹ is selected from the group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkenyl, substituted alkynyl, substituted cycloalkyl,substituted cycloalkenyl, aryl, heteroaryl and heterocyclic;

[1282] W, together with —C(H)_(p)C(═X)—, forms a cycloalkyl,cycloalkenyl, heterocyclic, substituted cycloalkyl, or substitutedcycloalkenyl group wherein each of said cycloalkyl, cycloalkenyl,heterocyclic, substituted cycloalkyl or substituted cycloalkenyl groupis optionally fused to form a bi- or multi-fused ring system (preferablyno more than 5 fused rings) with one or more ring structures selectedfrom the group consisting of cycloalkyl, cycloalkenyl, heterocyclic,aryl and heteroaryl group which, in turn, each of such ring structuresare optionally substituted with 1 to 4 substituents selected from thegroup consisting of hydroxyl, halo, alkoxy, substituted alkoxy,thioalkoxy, substituted thioalkoxy, nitro, cyano, carboxyl, carboxylesters, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, amino, N-alkylamino, N,N-dialkylamino,N-substituted alkylamino, N-alkyl N-substituted alkylamino,N,N-disubstituted alkylamino, —NHC(O)R⁴, —NHSO₂R⁴, —C(O)NH₂, —C(O)NHR⁴,—C(O)NR⁴R⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NHR⁴ and —S(O)₂NR⁴R⁴ where each R⁴is independently selected from the group consisting of alkyl,substituted alkyl, or aryl;

[1283] X is selected from the group consisting of oxo (═O), thiooxo(═S), hydroxyl (—H, —OH), thiol (H,—SH) and hydro (H,H);

[1284] Y is represented by the formula:

[1285] wherein each R² is independently selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl andheterocyclic;

[1286] Z is represented by the formula —T—CX′X″C(O)— where T is selectedfrom the group consisting of a bond covalently linking R¹ to —CX′X″—,oxygen, sulfur, —NR⁵ where R⁵ is hydrogen, acyl, alkyl, aryl orheteroaryl group;

[1287] X′ is hydrogen, hydroxy or fluoro,

[1288] X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form anoxo group;

[1289] m is an integer equal to 0 or 1;

[1290] n is an integer equal to 0, 1 or 2;

[1291] p is an integer equal to 0 or 1 such that when p is zero, thering defined by W and —C(H)_(p)C(═X)— is unsaturated at the carbon atomof ring attachment to Y and when p is one, the ring is saturated at thecarbon atom of ring attachment to Y,

[1292] with the following provisos:

[1293] A. when R¹ is 3,5-difluorophenyl, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a 2-(S)-indanol group;

[1294] B. when R¹ is phenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form atrans-2-hydroxy-cyclohex-1-yl group;

[1295] C. when R¹ is phenyl, Z is —CH₂C(O)—, m is 1, n is 0, and p is 1,then W, together with >CH and >C═X, does not form a gammabutyrolactonegroup or a 5,5-dimethyl-gammabutyrolactone group;

[1296] D. when R¹ is phenyl, Z is —CH₂C(O)—, m is 1, n is 0, and p is 1,then W, together with >CH and >C═X, does not form a e-caprolactam group;

[1297] E. when R¹ is cyclopropyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, nis 1, and p is 1, then W, together with >CH and >C═X, does not form anN-methylcaprolactam group;

[1298] F. when R¹ is 4-chlorobenzoyl-CH₂—, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform an 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one;

[1299] G. when R¹ is 2-phenylphenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1,n is 1, and p is 1, then W, together with >CH and >C═X, does not form an7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one;

[1300] H. when R¹ is CH₃OC(O)CH₂—, R² is —CH₃, Z is —CH₂C(O)—, m is 1, nis 1, and p is 1, then W, together with >CH and >C═X, does not form an2,3-dihydro-1-(t-butylC(O)CH₂—)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;

[1301] I. when R¹ is 4-ethoxyphenyl, 2,4,6-trimethylphenyl,4-phenylphenyl, CH₃OC(O)CH₂—, 4-HOCH₂-phenyl, 2,4,6-trifluorophenyl,2-trifluoromethyl-4-fluorophenyl, or CH₃S—, R² is —CH₃, Z is —CH₂C(O)—,m is 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²—)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;

[1302] J. when R¹ is 2,6-difluorophenyl, R² is —CH₃, Z is —CH(OH)C(O)—,m is 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²—)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,

[1303] K. when m is 1 and n is 1, then

[1304] does not equal cycloalkyl of from 3 to 8 carbon atoms optionallysubstituted with 1 to 3 alkyl groups.

[1305] The products of this invention include mixtures of R,Senantiomers at any stereochemical center. Preferably, however, when achiral product is desired, the chiral product corresponds to the L-aminoacid derivative. In the formulas set forth herein, a mixture of R,Senantiomers at the stereochemical center is sometimes indicated by asquiggly line as per convention. Other times, no stereochemicaldesignation is made at the stereochemical center and this also infersthat a mixture of enantiomers is present.

[1306] Preferred compounds described herein include those set forth inthe tables below: TABLE 1-1

Ex. R R′ X′/X″ R¹ 1-1 3,5-di-F-φ- H H,H —CH₃

[1307] TABLE 2-1

Ex. R X′/X″ R¹ R²/R³ n 2-1 3,5-di-F-φ- H,H —CH₃ forms a fused 1 phenylring 2-2 3,5-di-F-φ- H,H —CH₃ forms a fused 1 phenyl ring 2-33,5-di-F-φ- H,H —CH₃ forms a fused 1 phenyl ring 2-4 3,5-di-F-φ- H,H—CH₃ H,H 2 2-5 3,5-di-F-φ- H,H —CH₃ forms a fused 2 phenyl ring 2-63,5-di-F-φ- H,H —CH₃ forms a fused 3 phenyl ring

[1308] TABLE 2-2

Ex. R X′/X″ R¹ 2-6 3,5-di-F-φ- H,H —CH₃

[1309] TABLE 2-3

Ex. R X′/X″ R¹ 2-7 3,5-di-F-φ- H,H —CH₃

[1310] TABLE 3-1

Ex. R X′/X″ R¹ R²/R³ n 3-1 3,5-di-F-φ- H,H —CH₃ forms a fused 1 phenylring 3-2 φ- H,H —CH₃ forms a fused 2 phenyl ring

[1311] TABLE 3-2

Ex. R X′/X″ R¹ 3-3 3,5-di-F-φ- H,H —CH₃

[1312] TABLE 4-1

Ex. R′ R¹ R²/R³ R⁴ R⁵ n 4-1 3,5-di-F-φ-CH₂C(O)— —CH₃ H,H — — 0 4-23,4-di-Cl-φ- —CH₃ H,H — — 0 4-3 cyclopentyl-CH₂C(O)— —CH₃ forms a —CH₃—CH₃ 1 fused phenyl ring 4-4 3,5-di-F-φ-CH₂C(O)— —CH₃ forms a —CH₃ —CH₃1 fused phenyl ring

[1313] TABLE 5-1

R⁴/R^(4′) (R^(4′) when Ex. R′ R¹ R² R³ n = 2) R⁵ n 5-13,5-di-F-φ-CH₂C(O)— —CH₃ H H — H 0 5-2 3,5-di-F-φ-CH₂C(O)— —CH₃ H H H H1 5-3 3,5-di-F-φ-CH₂C(O)— —CH₃ H H H —CH₂φ 1 5-4 3,5-di-F-φ-CH₂C(O)——CH₃ —CH₃ H H,H H 2 5-5 3,5-di-F-φ-CH₂C(O)— —CH₃ H R³/R⁴ = — H 1 fusedphenyl ring 5-6 3,5-di-F-φ-CH₂C(O)— —CH₃ H R³/R⁴ = — —CH₂φ 1 fusedphenyl ring 5-7 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — H H 1 fused phenylring 5-8 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — H —CH₂φ 1 fused phenyl ring5-9 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — —CH₃ H 1 fused phenyl ring 5-103,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — -φ H 1 fused phenyl ring 5-113,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — H H 1 fused phenyl ring with 3-Fsubs. 5-12 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — H H 1 fused phenyl ringwith 4-F subs. 5-13 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — H —CH₂CH₂φ 1fused phenyl ring 5-14 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — H —CH₃ 1 fusedphenyl ring 5-15 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — H H 1 fused phenylring with 3-φ subs. 5-16 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — H H 1 fusedphenyl ring with 4-φ subs. 5-17 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ /R⁴ — — H1 together with the pendent atoms form (9-amino- fluroren-1- yl)glycineδ-lactam 5-18 φ-CH₂C(O)— —CH₃ H H H,H H 2 5-19 3,5-di-F-φ-CH₂C(O)— —CH₃H H H,H H 2 5-20 3,5-di-F-φ-CH₂C(O)— —CH₃ H H H,H —CH₂φ 2 5-213,5-di-F-φ-CH₂C(O)— —CH₃ H H H,H 2-methoxy- 2 ethoxy 5-223,5-di-F-φ-CH₂C(O)— —CH₃ H H H,H ethyl 2 5-23 3,5-di-F-φ-CH₂C(O)— —CH₃ Hethyl H,H H 2 5-24 3,5-di-F-φ-CH₂C(O)— —CH₃ H ethyl H,H H 2 5-253,5-di-F-φ-CH₂C(O)— —CH₃ H H H, H 2 benzyl 5-26 3,5-di-F-φ-CH₂C(O)— —CH₃R²/R³ = H H —CH₂φ 1 ethylene 5-27 cyclopentyl-CH₂C(O)— —CH₃ H H H,H—CH₂φ 2 5-28 cyclopentyl-CH₂C(O)— -φ H H H,H —CH₂φ 2 5-293,5-di-F-φ-CH₂C(O)— —CH₃ H H H,H —CH₂φ 2 5-30 cyclopentyl-CH₂C(O)— -φ HH H,H —CH₂φ 2 5-31 3,4-di-Cl-φ —CH₃ H H H,H H 2 5-32cyclopropyl-CH₂C(O)— -φ H H H,H —CH₃ 2 5-33 3,5-di-F-φ-CH₂C(O)— —CH₃ H HH,H H 4 H,H 5-34 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = H H H 1 fused phenylring with 4-benzyl subs. 5-35 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — —CH₂φ H1 fused phenyl ring 5-36 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — -φ —CH₃ 1fused phenyl ring 5-37 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — pyrid- H 1fused phenyl ring 5-38 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — pyrid- H 1fused phenyl ring 5-39 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — pyrid- H 1fused phenyl ring 5-40 3,5-di-F-φ-CH₂C(O)— —CH₃ R²/R³ = — — —CH₃ 0 fusedphenyl ring 5-41 3,5-di-F-φ-CH₂C(O)— —CH₃ -φ R³/R⁴ = — —CH₃ 1 (trans)fused phenyl ring 5-42 3,5-di-F-φ-CH₂C(O)— —CH₃ -φ R³/R⁴ = — —CH₃ 1(cis) fused phenyl ring 5-43 3,5-di-F-φ-CH₂C(O)— —CH₃ -φ R³/R⁴ = — H 1(trans) fused phenyl ring

[1314] TABLE 6-1

Ex. R′ R¹ R² R³ Q 6-1 3,5-di-F-φ-CH₂C(O)— —CH₃ —CH₃ H H 6-23,5-di-F-φ-CH₂C(O)— —CH₃ —CH₂CH₃ H F 6-16 3,5-di-F-φ-CH₂C(O)— —CH₃ H -φH

[1315] TABLE 6-2

Ex. R′ n R¹ R² R³ R⁴ 6-3 3,5-di-F-φ-CH₂C(O)— 0 — —CH₂CH₃ —CH₃ —CH₃ 6-43,5-di-F-φ-CH₂C(O)— 1 —CH₃ H H H 6-5 3,5-di-F-φ-CH₂C(O)— 1 —CH₃ —CH₂φ HH 6-6 cyclopentyl-CH₂C(O)— 0 — —CH₂CH₃ —CH₃ —CH₃ 6-7 3,5-di-F-φ-CH₂C(O)—1 —CH₃ —CH₃ H H 6-8 3,5-di-F-φ-CH₂C(O)— 0 —CH₃ —CH₃ —CH₃ H 6-93,5-di-F-φ-CH₂C(O)— 1 —CH₃ —CH₃ —CH₃ H 6-13 3,5-di-F-φ-CH₂C(O)— 1 —CH₃ H—CH₃ —CH₃ 6-14 3,5-di-F-φ-CH₂C(O)— 1 —CH₃ —CH₃ —CH₃ —CH₃ 6-153,5-di-F-φ-CH(OH)C(O)— 1 —CH₃ —CH₃ —CH₃ —CH₃ 6-17 3,5-di-F-φ-CH₂C(O)— 1—CH₃ —CH₂CH₃ —CH₃ —CH₃

[1316] TABLE 6-3

Ex. R′ R¹ R² Q′ 6-10 3,5-di-F-φ-CH₂C(O)— —CH₃ —CH₃ O 6-113,5-di-F-φ-CH₂C(O)— —CH₃ —CH₂CH₃ O 6-12 3,5-di-F-φ-CH₂C(O)— —CH₃ —CH₃ S

[1317] TABLE 7-1

Ex. R′ R¹ R² X X′ X″ 7-1  3,5-di-F-φ- —CH₃ —CH₃ H H H CH₂C(O)— 7-2 3,5-di-F-φ- —CH₃ —CH₃ H H H CH(OH)C(O)— 7-3  3,5-di-F-φ- —CH₃ —CH₃ H H HC(O)C(O)— 7-4  3,5-di-F-φ- —CH(CH₃)₂ —CH₃ H H H CH₂C(O)— 7-5 3,5-di-F-φ- —C(CH₃)₃ —CH₃ H H H CH₂C(O)— 7-6  3,5-di-F-φ- —CH(CH₃)₂ —CH₃H H H CH(OH)C(O)— 7-7  3,5-di-F-φ- —C(CH₃)₂ —CH₃ H H H CH(OH)C(O)— 7-8 3,5-di-F-φ- —CH₃ —CH₂C(O)OCH₃ H H H CH₂C(O)— 7-9  3,5-di-F-φ- —CH₃—CH₂C(O)OH H H H CH₂C(O)— 7-10 3,5-di-F-φ- —CH₃ —CH₂(O)C(CH₃)₃ H H HCH₂C(O)— 7-11 3,5-di-F-φ- —CH₃ —CH₂—C(O)- H H H CH₂C(O)— morpholin-4-yl7-12 (CH₃)₂CH— —CH₃ —CH₃ H H H CH(OH)C(O)— 7-13 cyclopentyl- —CH(CH₃)₂—CH₃ H H H CH(OH)C(O)— 7-14 (CH₃)₃C— —CH₃ —CH₃ H H H CH(OH)C(O)— 7-15cyclopentyl- —C(CH₃)₃ —CH₃ H H H CH(OH)C(O)— 7-16 cyclopentyl- —CH₃ —CH₃H H H CH(OH)C(O)— 7-17 3.5-di-F-φ- —CH₃ H H H H CH₂C(O)— 7-183,5-di-F-φ- —CH₃ —CH₂CH(CH₃)₂ H H H CH₂C(O)— 7-19 (CH₃)₂CH— —CH(CH₃)₂—CH₃ H H H CH(OH)C(O)— 7-20 (CH₃)₃C— —CH₃ —CH₃ H H H CH(OH)C(O)— 7-212-(φ)-φ- —CH₃ —CH₃ H H H 7-22 4-φ- —CH₃ —CH₃ H H H furazan-3-yl 7-243,5-di-F-φ- —CH₃ —(CH₂)₄φ H H H CH₂C(O)— 7-25 3,5-di-F-φ- —CH₃—CH₂-cyclopropyl H H H CH₂C(O)— 7-26 3,5-di-F-φ- —CH₃ —CH₂CF₃ H H HCH₂C(O)— 7-27 3,5-di-F-φ- —CH₃ cyclohexyl H H H CH₂C(O)— 7-283,5-di-F-φ- —CH₃ —CH₃ F H H CH(OH)C(O)— 7-29 3,5-di-F-φ- —CH₃ —CH₃ H H FCH(OH)C(O)— 7-30 3,5-di-F-φ- —CH₃ —CH₃ H F H CH(OH)C(O)— 7-313,5-di-F-φ- —CH₃ —CH₂-cyclopropyl H H H CH(OH)C(O)— 7-32 3,5-di-F-φ-—CH₃ —(CH₂)₄φ H H H CH(OH)C(O)— 7-33 3,5-di-F-φ- —CH(CH₃)₂—CH₂-cyclopropyl H H H CH(OH)C(O)— 7-34 3,5-di-F-φ- —CH(CH₃)₂ —(CH₂)₄φ HH H CH(OH)C(O)— 7-35 3,5-di-F-φ- —CH(CH₃)₂ hexyl H H H CH(OH)C(O)— 7-363,5-di-F-φ- —CH(CH₃)₂ —CH₃ H F H CH(OH)C(O)— 7-37 3,5-di-F-φ- —CH(CH₃)₂—CH₃ H H F CH(OH)C(O)— 7-38 3,5-di-F-φ- —CH(CH₃)₂ —CH₃ F H H CH(OH)C(O)—7-39 3,4-di-Cl-φ- -φ —CH₃ H H H

[1318] TABLE 7-2

Ex. R′ R¹ R² 7-23 3,5-di-F-φ —CH₃ —CH₃ CH₂C(O)—

[1319] TABLE 7C-1

Ex. R′ R¹ R² 7C-1 cyclopentylCH₂C(O)— —CH₃ —CH₃ 7C-2cyclopentylCH₂CH₂C(O)— —CH₃ —CH₃ 7C-3 cyclohexylCH₂C(O)— —CH₃ —CH₃ 7C-4(CH₃)₃CCH₂C(O)— —CH₃ —CH₃ 7C-5 φ-CH₂C(O)— —CH₃ —CH₃ 7C-6 3-Br-φ-CH₂C(O)——CH₃ —CH₃ 7C-7 3-F-φ-CH₂C(O)— —CH₃ —CH₃ 7C-8 3-Cl-φ-CH₂C(O)— —CH₃ —CH₃7C-9 3-CF₃-φ-CH₂C(O)— —CH₃ —CH₃ 7C-10 4-F-φ-CH₂C(O)— —CH₃ —CH₃ 7C-11CH₃(CH₂)₄C(O)— —CH₃ —CH₃ 7C-12 CH₃(CH₂)₃C(O)— —CH₃ —CH₃ 7C-133,4-di-F-φ-CH₂C(O)— —CH₃ —CH₃ 7C-14 cyclopropyl-CH₂C(O)— —CH₃ —CH₃ 7C-15cyclopent-1-enyl-CH₂C(O)— —CH₃ —CH₃ 7C-16 cyclohexyl-CH₂CH₂C(O)— —CH₃—CH₃ 7C-17 (CH₃)₂CHCH₂C(O)— —CH₃ —CH₃ 7C-18 (CH₃)₂CH═CH(CH₂)₂CH(CH₃)——CH₃ —CH₃ CH₂C(O)— 7C-19 φC(O)CH₂—CH₂C(O)— —CH₃ —CH₃ 7C-202-Cl-φ-CH₂C(O)— —CH₃ —CH₃ 7C-21 CH₂═CHCH₂—CH₂C(O)— —CH₃ —CH₃ 7C-22CH₃(CH₂)₃C(O)— —CH₃ —CH₃ 7C-23 thien-2-yl-CH₂C(O)— —CH₃ —CH₃ 7C-24thien-2-yl-(CH₂)₃C(O)— —CH₃ —CH₃ 7C-25 4-NO₂-φ-(CH₂)₃C(O)— —CH₃ —CH₃7C-26 2,4-di-F-φ-CH₂C(O)— —CH₃ —CH₃ 7C-27 2,6-di-F-φ-CH₂C(O)— —CH₃ —CH₃7C-28 4-(CH₃)₂CH-φ-CH₂C(O)— —CH₃ —CH₃ 7C-29 adamantan-1-yl-CH₂C(O)— —CH₃—CH₃ 7C-30 cyclohexyl-(CH₂)₄C(O)— —CH₃ —CH₃ 7C-31 CH₃SCH₂C(O)— —CH₃ —CH₃7C-32 thien-2-yl-(CH₂)₄C(O)— —CH₃ —CH₃ 7C-33 norbornan-2-yl-CH₂C(O)——CH₃ —CH₃ 7C-34 3,5-di-F-φ-CH₂C(O)— —CH₂CH(CH₂CH₃)₂ —CH₃ 7C-353,5-di-F-φ-CH₂C(O)— —CH₂CH(CH₃)CH₂CH₃ —CH₃ 7C-36 3,5-di-F-φ-CH₂C(O)——CH₂-cyclopropyl —CH₃ 7C-37 3,5-di-F-φ-CH₂C(O)— —CH₂CH₂-cyclohexyl —CH₃7C-38 3,5-di-F-φ-CH₂C(O)— —(CH₂)₅CH₂F —CH₃ 7C-39 3,5-di-F-φ-CH₂C(O)——CH₂CH(CH₃)CH₂CH₃ —CH₃ 7C-40 cyclohexyl-CH₂C(O)— —CH₂CH(CH₂CH₃)₂ —CH₃7C-41 cyclopropyl-CH₂C(O)— —CH₂CH(CH₂CH₃)₂ —CH₃ 7C-42 (CH₃)₂CHCH₂C(O)——CH₂CH(CH₂CH₃)₂ —CH₃ 7C-43 3-CF₃-φ-CH₂C(O)— —CH₂CH(CH₂CH₃)₂ —CH₃ 7C-443,4-di-F-φ-CH₂C(O)— —CH₂CH(CH₂CH₃)₂ —CH₃ 7C-45 2,4-di-F-φ-CH₂C(O)——CH₂CH(CH₂CH₃)₂ —CH₃ 7C-46 3-F-φ-CH₂C(O)— —CH₂CH(CH₃)CH₂CH₃ —CH₃ 7C-47cyclopentyl-CH₂C(O)— —CH₂CH(CH₃)CH₂CH₃ —CH₃ 7C-48 cyclohexyl-CH₂C(O)——CH₂CH(CH₃)CH₂CH₃ —CH₃ 7C-49 cyclopropyl-CH₂C(O)— —CH₂CH(CH₃)CH₂CH₃ —CH₃7C-50 thien-2-yl-CH₂C(O)— —CH₂CH(CH₃)CH₂CH₃ —CH₃ 7C-51 (CH₃)₂CHCH₂C(O)——CH₂CH(CH₃)CH₂CH₃ —CH₃ 7C-52 3-CF₃-φ-CH₂C(O)— —CH₂CH(CH₃)CH₂CH₃ —CH₃7C-53 4-F-φ-CH₂C(O)— —CH₂CH(CH₃)CH₂CH₃ —CH₃ 7C-54 3,4-di-F-φ-CH₂C(O)——CH₂CH(CH₃)CH₂CH₃ —CH₃ 7C-55 2,4-di-F-φ-CH₂C(O)— —CH₂CH(CH₃)CH₂CH₃ —CH₃7C-56 3-F-φ-CH₂C(O)— —CH₂CH₂cyclohexyl —CH₃ 7C-57 cyclopentyl-CH₂C(O)——CH₂CH₂cyclohexyl —CH₃ 7C-58 cyclohexyl-CH₂C(O)— —CH₂CH₂cyclohexyl —CH₃7C-59 cyclopropyl-CH₂C(O)— —CH₂CH₂cyclohexyl —CH₃ 7C-60 (CH₃)₂CHCH₂C(O)——CH₂CH₂cyclohexyl —CH₃ 7C-61 4-F-φ-CH₂C(O)— —CH₂CH₂cyclohexyl —CH₃ 7C-623,4-F-φ-CH₂C(O)— —CH₂CH₂cyclohexyl —CH₃ 7C-63 2,4-F-φ-CH₂C(O)——CH₂CH₂cyclohexyl —CH₃ 7C-64 3-F-φ-CH₂C(O)— —(CH₂)₅CH₂F —CH₃ 7C-65cyclopentyl-CH₂C(O)— —(CH₂)₅CH₂F —CH₃ 7C-66 cyclohexyl-CH₂C(O)——(CH₂)₅CH₂F —CH₃ 7C-67 cyclopropyl-CH₂C(O)— —(CH₂)₅CH₂F —CH₃ 7C-68(CH₃)₂CHCH₂C(O)— —(CH₂)₅CH₂F —CH₃ 7C-69 3-CF₃-φ-CH₂C(O)— —(CH₂)₅CH₂F—CH₃ 7C-70 4-F-φ-CH₂C(O)— —(CH₂)₅CH₂F —CH₃ 7C-71 3,4-F-φ-CH₂C(O)——(CH₂)₅CH₂F —CH₃ 7C-72 2,4-F-φ-CH₂C(O)— —(CH₂)₅CH₂F —CH₃ 7C-734-CH₃O-φ-CH₂C(O)— —CH₃ —CH₃ 7C-74 4-CH₃O-φ-CH₂CH₂C(O)— —CH₃ —CH₃ 7C-75naphth-1-yl-CH₂C(O)— —CH₃ —CH₃ 7C-76 3,4-methylenedioxy-φ-CH₂C(O)— —CH₃—CH₃ 7C-77 φ-CH₂CH₂C(O)— —CH₃ —CH₃ 7C-78 CH₃(CH₂)₆C(O)— —CH₃ —CH₃ 7C-793-HO-φ-CH₂CH₂C(O)— —CH₃ —CH₃ 7C-80 4-CH₃-φ-CH₂CH₂C(O)— —CH₃ —CH₃ 7C-814-Cl-φ-CH₂CH₂C(O)— —CH₃ —CH₃ 7C-82 CH₃CH(φ)CH₂C(O)— —CH₃ —CH₃ 7C-834-HO-φ-CH₂CH₂C(O)— —CH₃ —CH₃ 7C-84 3,4,5-tri-F-φ-CH₂C(O)— —CH₃ —CH₃7C-85 4-CH₃O-φ-CH₂CH₂CH₂C(O)— —CH₃ —CH₃ 7C-86 CH₃OC(O)CH₂CH₂C(O)— —CH₃—CH₃ 7C-87 φ-CH₂CH₂CH₂C(O)— —CH₃ —CH₃ 7C-88 φ-CH₂—S—CH₂CH₂C(O)— —CH₃—CH₃ 7C-89 CH₃CH₂CH(CH₃)CH₂C(O)— —CH₃ —CH₃ 7C-90 CH₃OC(O)(CH₂)₆C(O)——CH₃ —CH₃ 7C-91 indan-2-yl-CH₂C(O)— —CH₃ —CH₃ 7C-92 CH₃OC(O)(CH₂)₄C(O)——CH₃ —CH₃ 7C-93 (2-methylbenzofuran-3-yl)CH₂C(O)— —CH₃ —CH₃ 7C-94CH₃CH₂C(O)— —CH₃ —CH₃ 7C-95 CH₃OCH₂CH₂C(O)— —CH₃ —CH₃ 7C-964-F-φ-CH₂CH₂C(O)— —CH₃ —CH₃ 7C-97 4-F-φ-OCH₂CH₂C(O)— —CH₃ —CH₃ 7C-99CH₃CH═CHCH₂C(O)— —CH₃ —CH₃ 7C-100 2,4-di-Cl-φ-O—(CH₂)₃C(O)— —CH₃ —CH₃7C-101 2,3-di-Cl-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-102 4-Cl-φC(O)—CH₂CH₂C(O)——CH₃ —CH₃ 7C-103 4-F-φ-NHC(O)CH₂CH₂C(O)— —CH₃ —CH₃ 7C-104(φ)₂CHNHC(O)CH₂CH₂CH₂C(O)— —CH₃ —CH₃ 7C-105 2-F-φ-CH₂—C(O)— —CH₃ —CH₃7C-107 φ-NHC(O)CH₂CH₂C(O)— —CH₃ —CH₃ 7C-108 2,4-di-Cl-φ-O—CH₂C(O)— —CH₃—CH₃ 7C-109 2-NO₂-φ-CH₂—C(O)— —CH₃ —CH₃ 7C-110 CH₃(CH₂)₂CH(φ)CH₂C(O)——CH₃ —CH₃ 7C-111 2,4-di-CH₃-φ-C(O)(CH₂)₂C(O)— —CH₃ —CH₃ 7C-1122-F-3-CF₃-φ-CH₂C(O)— —CH₃ —CH₃ 7C-113 2,4,6-tri-F-φ-CH₂C(O)— —CH₃ —CH₃7C-114 4-F-2-CF₃-φ-CH₂C(O)— —CH₃ —CH₃ 7C-115 2-F-4-CF₃-φ-CH₂C(O)— —CH₃—CH₃ 7C-116 4-HO-φ-CH₂C(O)— —CH₃ —CH₃ 7C-117 4-CH₃O-φ-O—CH₂C(O)— —CH₃—CH₃ 7C-118 2-CH₃O-φ-CH₂C(O)— —CH₃ —CH₃ 7C-119 2-Br-φ-CH₂C(O)— —CH₃ —CH₃7C-120 4-(φ-CH₂O-)φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-121 4-HO-φ-O—CH₂C(O)— —CH₃—CH₃ 7C-122 CH₃C(O)CH₂CH₂C(O)— —CH₃ —CH₃ 7C-123 2-HO-φ-CH₂C(O)— —CH₃—CH₃ 7C-124 3,4-di-CH₃O-φ-CH₂C(O)— —CH₃ —CH₃ 7C-1254-CH₃O-φ(CO)—CH₂CH₂C(O)— —CH₃ —CH₃ 7C-126 φ(CO)—CH₂CH₂C(O)— —CH₃ —CH₃7C-127 3-HO-φ-CH₂C(O)— —CH₃ —CH₃ 7C-128 CH₃C(O)N(φ)CH₂C(O)— —CH₃ —CH₃7C-129 thien-3-yl-CH₂C(O)— —CH₃ —CH₃ 7C-130 φ-(CH₂)₅C(O)— —CH₃ —CH₃7C-131 cyclohexyl-(CH₂)₃C(O)— —CH₃ —CH₃ 7C-132 2,3,5-tri-F-φ-CH₂C(O)——CH₃ —CH₃ 7C-133 2,4,5-tri-F-φ-CH₂C(O)— —CH₃ —CH₃ 7C-134 CH₃═CHCH₂C(O)——CH₃ —CH₃ 7C-135 CH₃S(CH₂)₂C(O)— —CH₃ —CH₃ 7C-136 3-NO₂-φ-CH₂C(O)— —CH₃—CH₃ 7C-137 (CH₃)₃CNHC(O)CH₂CH₂C(O)— —CH₃ —CH₃ 7C-138 4-Br-φ-CH₂C(O)——CH₃ —CH₃ 7C-139 4-F-φC(O)—CH₂CH₂C(O)— —CH₃ —CH₃ 7C-1402-Cl-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-141 4-CH₃-φ-CH₂C(O)— —CH₃ —CH₃ 7C-1423-CH₃-φ-CH₂C(O)— —CH₃ —CH₃ 7C-143 3,4-di-Cl-φ-CH₂C(O)— —CH₃ —CH₃ 7C-1444-Cl-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-145 3-CH₃-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-1464-(CH₃)₂CH-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-147 4-(φ-O)-φ-CH₂C(O)— —CH₃ —CH₃7C-148 φSCH₂C(O)— —CH₃ —CH₃ 7C-149 4-C₂H₅O-φ-CH₂C(O)— —CH₃ —CH₃ 7C-1502,5-di-CH₃O-φ-CH₂C(O)— —CH₃ —CH₃ 7C-151 2-CH₃-φ-CH₂C(O)— —CH₃ —CH₃7C-152 (φ)₂CHCH₂C(O)— —CH₃ —CH₃ 7C-153 φOCH₂CH₂C(O)— —CH₃ —CH₃ 7C-1544-CF₃-φ-CH₂C(O)— —CH₃ —CH₃ 7C-155 4-CH₃-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-1562-(φ-O)-φ-CH₂C(O)— —CH₃ —CH₃ 7C-157 3-(φ-O)-φ-CH₂C(O)— —CH₃ —CH₃ 7C-1583,4-di-Cl-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-159 4-F-φ-O—CH₂C(O)— —CH₃ —CH₃7C-160 3,4,5-tri-CH₃O-φ-CH₂C(O)— —CH₃ —CH₃ 7C-161 2,4-di-Cl-φ-CH₂C(O)——CH₃ —CH₃ 7C-162 thianaphthen-4-yl-CH₂C(O)— —CH₃ —CH₃ 7C-163CH₃OCH₂C(O)— —CH₃ —CH₃ 7C-164 C₂H₅OCH₂C(O)— —CH₃ —CH₃ 7C-165 φOCH₂C(O)——CH₃ —CH₃ 7C-166 3-CH₃O-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-167 4-C₄H₉O-φ-CH₂C(O)——CH₃ —CH₃ 7C-168 2-CH₃O-φ-CH₂CH₂C(O)— —CH₃ —CH₃ 7C-169(CH₃)₂NC(O)CH₂CH₂C(O)— —CH₃ —CH₃ 7C-170 3,4-methylenedioxy-φ-CH₂CH₂C(O)——CH₃ —CH₃ 7C-171 2-Cl-6-F-φ-CH₂C(O)— —CH₃ —CH₃ 7C-1722,5-di-F-φ-CH₂C(O)— —CH₃ —CH₃ 7C-173 2,3,4,5,6-penta-F-φ-O—CH₂C(O)— —CH₃—CH₃ 7C-174 3,5-di-CF₃-φ-CH₂C(O)— —CH₃ —CH₃ 7C-1753,5-di-CH₃-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-176 4-Cl-φ-CH₂C(O)— —CH₃ —CH₃7C-177 3-Cl-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-178 benzo[b]thien-3-yl-CH₂C(O)——CH₃ —CH₃ 7C-179 3,5-di-CH₃O-φ-CH₂C(O)— —CH₃ —CH₃ 7C-1802,5-di-CH₃-φ-CH₂C(O)— —CH₃ —CH₃ 7C-181 2,4,6-tri-CH₃-φ-CH₂C(O)— —CH₃—CH₃ 7C-182 4-(φ)-φ-CH₂C(O)— —CH₃ —CH₃ 7C-183 (CH₃)₃COC(O)NH(CH₂)₂C(O)——CH₃ —CH₃ 7C-184 trans-styryl-CH₂C(O)— —CH₃ —CH₃ 7C-185H₂NC(O)(CH₂)₃C(O)— —CH₃ —CH₃ 7C-186 2-Cl-φ-CH₂CH₂C(O)— —CH₃ —CH₃ 7C-187CH₃CH₂CH₂C(O)— —CH₃ —CH₃ 7C-188 CH₃CH₂CH═CHCH₂C(O)— —CH₃ —CH₃ (trans)7C-189 φ(CH₂)₄C(O)— —CH₃ —CH₃ 7C-190 3-CH₃O-φ-CH₂CH₂C(O)— —CH₃ —CH₃7C-191 4-Cl-φ-CH(CH₃)CH₂C(O)— —CH₃ —CH₃ 7C-192 CH₃CH(CF₃)CH₂C(O)— —CH₃—CH₃ 7C-194 naphthalen-1-yl-O—CH₂C(O)— —CH₃ —CH₃ 7C-1962-(CF₃)-φ-C(O)CH₂CH₂C(O)— —CH₃ —CH₃ 7C-197 φC(O)NHCH(φ)CH₂CH₂C(O)— —CH₃—CH₃ 7C-198 CH₃CH(═NHOH)CH₂CH₂C(O)— —CH₃ —CH₃ 7C-1994-CH₃-φ-NHC(O)CH₂CH₂CH₂C(O)— —CH₃ —CH₃ 7C-200 4-(C₂H₅-φ-O)φ-O—CH₂C(O)——CH₃ —CH₃ 7C-201 φC(O)CH(φ)CH₂CH₂C(O)— —CH₃ —CH₃ 7C-2024-(HOCH₂)-φ-O—CH₂C(O)— —CH₃ —CH₃ 7C-203 CF₃(CH₂)₂C(O)— —CH₃ —CH₃ 7C-204(CH₃)₂CHC(O)NHCH(φ)CH₂C(O)— —CH₃ —CH₃ 7C-205 2-CH₃-φ-O—CH₂C(O)— —CH₃—CH₃ 7C-206 φSO₂CH₂CH₂C(O)— —CH₃ —CH₃ 7C-207 4-NO₂-φ-CH₂C(O)— —CH₃ —CH₃7C-208 C₂H₅OCH₂CH₂C(O)— —CH₃ —CH₃ 7C-209 2,3-di-F-φ-CH(OH)C(O)— —CH₃—CH₃ 7C-210 2,6-di-F-φ-CH(OH)C(O)— —CH₃ —CH₃ 7C-211 4-F-φ-CH(OH)C(O)——CH₃ —CH₃ 7C-212 2,5-di-F-φ-CH(OH)C(O)— —CH₃ —CH₃ 7C-213φ-CH₂CH(OH)C(O)— —CH₃ —CH₃ 7C-214 φ-CH(OH)C(O)— —CH₃ —CH₃ 7C-2154-Cl-φ-CH(OH)C(O)— —CH₃ —CH₃ 7C-216 (CH₃)₂CHCH₂CH(OH)C(O)— —CH₃ —CH₃7C-217 4-Br-φ-CH(OH)C(O)— —CH₃ —CH₃ 7C-218 CH₃CH(OH)C(O)— —CH₃ —CH₃7C-219 φ-CH₂CH(OH)C(O)— —CH₃ —CH₃ 7C-220 (CH₃)₂CHCH₂CH₂CH₂C(O)— —CH₃—CH₃ 7-C221 3,5-di-F-φ-CH₂C(O)— —CH₂CH₂SCH₃ —CH₃ 7-C2223,5-di-F-φ-CH₂C(O)— -φ —CH₃ 7-C223 3,5-di-F-φ-CH₂C(O)— —CH₂CH(CH₃)₂ —CH₃7-C224 3,5-di-F-φ-CH₂C(O)— cyclohexyl —CH₃ 7-C225 3,5-di-F-φ-CH₂C(O)——CH(OH)CH₃ —CH₃ 7-C226 3,5-di-F-φ-CH₂C(O)— thien-2-yl —CH₃ 7-C227thien-2-yl-CH₂C(O)— —CH₂CH₂SCH₃ —CH₃ 7-C228 thien-2-yl-CH₂C(O)— -φ —CH₃7-C229 thien-2-yl-CH₂C(O)— —CH₂CH(CH₃)₂ —CH₃ 7-C230 thien-2-yl-CH₂C(O)—cyclohexyl —CH₃ 7-C231 thien-2-yl-CH₂C(O)— —CH(OH)CH₃ —CH₃ 7-C232thien-2-yl-CH₂C(O)— thien-2-yl —CH₃ 7-C233 (CH₃)₂CHCH₂C(O)— —CH₂CH₂SCH₃—CH₃ 7-C234 (CH₃)₂CHCH₂C(O)— -φ —CH₃ 7-C235 (CH₃)₂CHCH₂C(O)——CH₂CH(CH₃)₂ —CH₃ 7-C236 (CH₃)₂CHCH₂C(O)— cyclohexyl —CH₃ 7-C237(CH₃)₂CHCH₂C(O)— —CH(OH)CH₃ —CH₃ 7-C238 (CH₃)₂CHCH₂C(O)— thien-2-yl —CH₃7-C239 φ-CH₂C(O)— —CH₂CH₂SCH₃ —CH₃ 7-C240 φ-CH₂C(O)— -φ —CH₃ 7-C241φ-CH₂C(O)— —CH₂CH(CH₃)₂ —CH₃ 7-C242 φ-CH₂C(O)— cyclohexyl —CH₃ 7-C243φ-CH₂C(O)— —-CH(OH)CH₃ —CH₃ 7-C244 φ-CH₂C(O)— thien-2-yl —CH₃

[1320] TABLE 8-1

R² = 1 position; R³ = 5 position; R⁴ = 7 position Ex. R R′ X′/X″ R¹ R²R³ R⁴ n 8-1 3,5-di-F-φ- — H, H — —CH₃ -φ H 0 8-2 3,5-di-F-φ- H H, H —CH₃—CH₂CH₃ -φ H 1 8-3 3,5-di-F-φ- H H, H —CH₃ H -φ H 1 8-4 3,5-di-F-φ- H H,H —CH₃ —CH₃ piperidin- H 1 1-yl 8-5 3,5-di-F-φ- H H, H —CH₃ —CH₃ -φ Cl 18-6 3,5-di-F-φ- H H, H —CH₃ —CH₃ 2-F-φ- Br 1 8-7 3,5-di-F-φ- —CH₃ H, H—CH₃ —CH₃ -φ H 1 8-8 3,5-di-F-φ- H H, H —CH₃ —CH₃ 2-Cl-φ- Cl 1 8-93,5-di-F-φ- H H, H —CH₃ —CH₃ cyclohexyl H 1 8-10 3,5-di-F-φ- H H, H —CH₃—CH₃ -φ NO₂ 1 8-11 3,5-di-F-φ- H H, H —CH₃ —CH₃ 2-F-φ- H 1 8-123,5-di-F-φ- H OH, H —CH(CH₃)₂ —CH₃ -φ H 1 8-13 3,5-di-F-φ- H OH, H—C(CH₃)₃ —CH₃ -φ H 1 8-14 3,5-di-F-φ- H H, H —CH₃ —CH₃ 3-F-φ- H 1 8-153,5-di-F-φ- H H, H —CH₃ —CH₃ 4-F-φ- H 1 8-16 cyclopentyl H OH, H —CH₃—CH₃ -φ H 1 8-17 cyclopentyl H OH, H —CH(CH₃)₂ —CH₃ -φ H 1 8-183,5-di-F-φ- H H, H —CH₃ —CH₃ —CH₃ H 1 8-19 3,5-di-F-φ- H H, H —CH₃—CH₂CH(CH₃)₂ -φ H 1 8-20 3,5-di-F-φ- H OH, H —CH₃ —CH₃ -φ H 1 8-213,5-di-F-φ- H ═O —CH₃ —CH₃ -φ H 1 8-22 CH₃S— H H, H —CH₃ —CH₃ -φ H 18-23 3,5-di-F-φ- H H, H —CH(CH₃)₂ —CH₃ -φ H 1 8-24 3,5-di-F-φ- H H, H—C(CH₃)₃ —CH₃ -φ H 1 8-25 3,5-di-F-φ- H H, H —CH₃ —CH(CH₃)₂ -φ H 1 8-263,5-di-F-φ- H H, H —CH₃ 1-cyclopropyl- -φ H 1 methyl 8-27 3,5-di-F-φ- HF, H —CH₃ —CH₃ -φ H 1 8-28 3,5-di-F-φ- H H, H —CH₃ —CH₂CH₂CH₃ -φ H 18-29 (CH₃)₂CH— H H, H -φ —CH₃ -φ H 1 8-30 3,5-di-F-φ- H H, H -φ —CH₃ -φH 1 8-31 φ-S— H H, H —CH₃ —CH₃ -φ H 1 8-32 (CH₃)₂CH— H H, H —CH₃ —CH₃ -φH 1 8-33 φ-S— H H, H -φ —CH₃ -φ H 1 8-34 4-CH₃O-φ- H H, H —CH₃ —CH₃ -φ H1 CH₂— 8-35 3-Br-φ- H H, H —CH₃ —CH₃ -φ H 1 8-36 cyclohexyl- H H, H —CH₃—CH₃ -φ H 1 CH₂CH₂— 8-37 4-CH₃O-φ- H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-38(CH₃)₂CH— H OH, H —CH₃ —CH₃ -φ H 1 8-39 (CH₃)₂CH— H OH, H —CH(CH₃)₂ —CH₃-φ H 1 8-40 (CH₃)₃C— H OH, H —CH₃ —CH₃ -φ H 1 8-41 2-thienyl H H, H —CH₃—CH₃ 2-pyridyl H 1 8-42 3,5-di-F-φ- H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-433-Br-φ- H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-44 φ-S— H H, H —CH₃ —CH₃2-pyridyl H 1 8-45 4-CH₃CH₂O-φ- H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-464-CF₃-φ- H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-47 3,5-di-CF₃-φ- H H, H —CH₃—CH₃ 2-pyridyl H 1 8-48 CH₃S— H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-49cyclohexyl H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-50 2,3,4,5,6- H H, H —CH₃—CH₃ 2-pyridyl H 1 penta-F-φ-O- 8-51 3-thio- H H, H —CH₃ —CH₃ 2-pyridylH 1 naphthalyl 8-52 2,4,6-tri- H H, H —CH₃ —CH₃ 2-pyridyl H 1 CH₃-φ-8-53 (4-φ)-φ H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-54 3,4-di-F-φ- H H, H —CH₃—CH₃ 2-pyridyl H 1 8-55 2-thienyl- H H, H —CH₃ —CH₃ 2-pyridyl H 1CH₂CH₂— 8-56 (CH₃)₂CH— H H, H —CH₃ —CH₃ 2-pyridyl H 1 CH₂CH₂— 8-57CH₃OC(O)CH₂— H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-60 2,6-di-F-φ- H OH, H—CH₃ —CH₃ 2-pyridyl H 1 8-61 4-F-φ- H OH, H —CH₃ —CH₃ 2-pyridyl H 1 8-622,5-di-F-φ- H OH, H —CH₃ —CH₃ 2-pyridyl H 1 8-63 2,4,6-tri-F-φ- H H, H—CH₃ —CH₃ 2-pyridyl H 1 8-64 2-CF₃-4-F-φ- H H, H —CH₃ —CH₃ 2-pyridyl H 18-65 CF₃CH₂— H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-66 (4-(CH₃)₂CH—) H H, H—CH₃ —CH₃ 2-pyridyl H 1 φ- 8-67 φ-CH₂— H OH, H —CH₃ —CH₃ 2-pyridyl H 18-68 φ- H OH, H —CH₃ —CH₃ 2-pyridyl H 1 8-69 4-Cl-φ- H OH, H —CH₃ —CH₃2-pyridyl H 1 8-70 (CH₃)₂CH— H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-712,3,5-tri-F-φ- H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-72 CH₃S—CH₂— H H, H —CH₃—CH₃ 2-pyridyl H 1 8-73 (CH₃)₂CH— H OH, H —CH₃ —CH₃ 2-pyridyl H 1 8-743-NO₂-φ- H H, H —CH₃ —CH₃ 2-pyridyl H 1 8-75 4-CH₃O-φ- H H, H —CH₃(CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-76 2-thienyl H H, H —CH₃ (CH₃)₃CC(O)—2-pyridyl H 1 CH₂— 8-77 3,5-di-F-φ- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H1 CH₂— 8-78 3-Br-φ- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-79φ-S— H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-80 4-CH₃CH₂O— H H, H—CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 φ- CH₂— 8-81 4-CF₃-φ- H H, H —CH₃(CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-82 3,5-di-CF₃-φ- H H, H —CH₃(CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-83 CH₃S— H H, H —CH₃ (CH₃)₃CC(O)—2-pyridyl H 1 CH₂— 8-84 cyclohexyl H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H1 CH₂— 8-85 2,3,4,5,6- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1penta-F-φ-O— CH₂— 8-86 3-thio- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1naphthalyl CH₂— 8-87 2,4,6-tri-CH₃— H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H1 φ- CH₂— 8-88 (4-φ)-φ- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-893,4-di-F-φ- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-90 thien-2-yl-H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂CH₂— CH₂— 8-91 (CH₃)₂CH(CH₂)₂—H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-92 CH₃OC(O)CH₂— H H, H—CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-95 2,6-di-F-φ H OH, H —CH₃(CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-96 4-F-φ- H OH, H —CH₃ (CH₃)₃CC(O)—2-pyridyl H 1 CH₂— 8-97 2,5-di-F-φ- H OH, H —CH₃ (CH₃)₃CC(O)— 2-pyridylH 1 CH₂— 8-98 2,4,6-tri-F-φ- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂—8-99 2-CF₃-4-F-φ- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-100CF₃CH₂— H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-101 4-(CH₃)₂CH-φ-H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-102 φCH₂— H OH, H —CH₃(CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-103 φ- H OH, H —CH₃ (CH₃)₃CC(O)—2-pyridyl H 1 CH₂— 8-104 4-Cl-φ- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1CH₂— 8-105 (CH₃)₂CH— H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-1062,3,5-tri-F-φ- H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-107CH₃S—CH₂— H H, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-108 (CH₃)₂CH— HOH, H —CH₃ (CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-109 3-NO₂-φ- H H, H —CH₃(CH₃)₃CC(O)— 2-pyridyl H 1 CH₂— 8-110 4-CH₃O-φ- H H, H —CH₃ (CH₃CH₂)₂N—2-pyridyl H 1 CH₂CH₂— 8-111 2-thienyl H H, H —CH₃ (CH₃CH₂)₂N— 2-pyridylH 1 CH₂CH₂— 8-112 3,5-di-F-φ- H H, H —CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1CH₂CH₂— 8-113 3-Br-φ- H H, H —CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂—8-114 φ-S— H H, H —CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-115(4-CH₃CH₂O)-φ- H H, H —CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-116 CH₃S—H H, H —CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-117 cyclohexyl H H, H—CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-118 2,3,4,5,6- H H, H —CH₃(CH₃CH₂)₂N— 2-pyridyl H 1 penta-F-φ-O— CH₂CH₂— 8-119 3-thio- H H, H —CH₃(CH₃CH₂)₂N— 2-pyridyl H 1 naphthalyl CH₂CH₂— 8-120 φ- H ═O —CH₃(CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-121 2,4,6-tri-CH₃— H H, H —CH₃(CH₃CH₂)₂N— 2-pyridyl H 1 φ- CH₂CH₂— 8-122 (4-φ)-φ- H H, H —CH₃(CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-123 3,4-di-F-φ- H H, H —CH₃(CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-124 thien-2-yl- H H, H —CH₃(CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— CH₂CH₂— 8-125 (CH₃)₂CH(CH₂)₂— H H, H—CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-126 CH₃OC(O)CH₂— H H, H —CH₃(CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-129 2,6-di-F-φ- H OH, H —CH₃(CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-130 4-F-φ- H OH, H —CH₃ (CH₃CH₂)₂N—2-pyridyl H 1 CH₂CH₂— 8-131 2,5-di-F-φ- H OH, H —CH₃ (CH₃CH₂)₂N—2-pyridyl H 1 CH₂CH₂— 8-132 4-HOCH₂-φ-O— H H, H —CH₃ (CH₃CH₂)₂N—2-pyridyl H 1 CH₂CH₂— 8-133 2,4,6-tri-F-φ- H H, H —CH₃ (CH₃CH₂)₂N—2-pyridyl H 1 CH₂CH₂— 8-134 2-CF₃-4-F-φ- H H, H —CH₃ (CH₃CH₂)₂N—2-pyridyl H 1 CH₂CH₂— 8-135 CF₃CH₂— H H, H —CH₃ (CH₃CH₂)₂N— 2-pyridyl H1 CH₂CH₂— 8-136 (CH₃)₂CH-φ- H H, H —CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1CH₂CH₂— 8-137 φCH₂— H OH, H —CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-138φ- H OH, H —CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-139 4-Cl-φ- H OH, H—CH₃ (CH₃CH₂)₂N— 2-pyridyl H 1 CH₂CH₂— 8-166 3,5-di-F-φ- H H, H —CH₃—CH₃ -φ H 1

[1321] TABLE 8-2

R² = 1 position; R³ = 5 position; R⁴ = 7 position Ex. R X′/X″ R′ R¹ R²R³ R⁴ n 8-140 3,5-di-F-φ- OH, H H thien-3- —CH₂C(CH₃)₃ —CH₂C(CH₃)₃ H 1yl 8-141 3,5-di-F-φ- OH, H H —CH₃ -φ —CH₃ H 1 8-142 3,5-di-F-φ- OH, H H—CH₃ —CH₃ -φ H 1 8-146 3,5-di-F-φ- H, H H —CH₃ —CH(CH₃)₂ —CH(CH₃)₂ H 18-147 3,5-di-F-φ- H, H H 2-thienyl —CH(CH₃)₂ —CH(CH₃)₂ H 1 8-148cyclopropyl H, H H 2-thienyl —CH(CH₃)₂ —CH(CH₃)₂ H 1 8-149 cyclopentylH, H H 2-thienyl —CH(CH₃)₂ —CH(CH₃)₂ H 1 8-150 3,5-di-F-φ- H, H H —CH₃—CH₃ —CH₃ H 1 8-151 3,5-di-F-φ- OH, H H —CH₃ —CH₃ —CH₃ H 1 8-1523,5-di-F-φ- H, H H —CH₃ —CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ H 1 8-153 cyclopentylH, H H —CH₃ —CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ H 1 8-154 cyclopropyl H, H H —CH₃—CH₂CH(CH₃)₂ —CH₂CH(CH₃)₂ H 1 8-155 3,5-di-F-φ- H, H H -φ —CH₂CH(CH₃)₂—CH₂CH(CH₃)₂ H 1 8-156 3,5-di-F-φ- H, H H —CH₃ 1-cyclopropyl-1-cyclopropyl- H 1 methyl methyl 8-157 cyclopentyl H, H H —CH₃1-cyclopropyl- 1-cyclopropyl- H 1 methyl methyl 8-158 cyclopentyl OH, HH —CH₃ 1-cyclopropyl- 1-cyclopropyl- H 1 methyl methyl 8-159 3,5-di-F-φ-H, H H —CH₃ —CH₂C(CH₃)₃ —CH₂C(CH₃)₃ H 1 8-160 3,5-di-F-φ- OH, H H —CH₃—CH₂C(CH₃)₃ —CH₂C(CH₃)₃ H 1 8-161 cyclopentyl H, H H —CH₃ —CH₂C(CH₃)₃—CH₂C(CH₃)₃ H 1 8-162 cyclopentyl OH, H H —CH₃ —CH₂C(CH₃)₃ —CH₂C(CH₃)₃ H1 8-163 3,5-di-F-φ- H, H H —CH₃ -φ -φ H 1 8-164 cyclopentyl H, H H —CH₃-φ -φ H 1 8-165 cyclopentyl OH, H H —CH₃ -φ -φ H 1

[1322] TABLE 8-3

R² = 1 position; R³ = 5 position; R⁴ = 7 position Ex. R X′/X″ R′ R¹ R²R³ R⁴ n 8-142 3,5-di-F-φ- OH, H H —CH₃ —CH₃ -φ H 1

[1323] TABLE 8-4

Ex. R X′/X″ R¹ R² A-B 8-143 3,5-di-F-φ- H, H —CH₃ -φ —CH═CH— 8-1443,5-di-F-φ- H, H —CH₃ -φ —CH₂—CH₂— 8-145 3,5-di-F-φ- H, H —CH₃ -φ —N═CH—

[1324] TABLE 8-5

Ex. R X′/X″ R¹ R² 8-167 3,5-di-F-φ- H, OH —CH₃ —CH₃

[1325] TABLE 8C-1

R² = 1 position; R³ = 5 position; R⁴ = 7 position X and Iso. R X′ R¹ R²R³ R⁴ (at *) 3,4-methylenedioxy-φ- H, H —CH₃ —CH₃ -φ H R, S 2-CH₃O-φ-O—H, H —CH₃ —CH₃ -φ H R, S 4-[(CH₃)₂CH]φ-O— H, H —CH₃ —CH₃ -φ H R, SCH₃CH₂O— H, H —CH₃ —CH₃ -φ H R, S 4-(φ-O-)φ- H, H —CH₃ —CH₃ -φ H R, S4-CH₃CH₂O-φ- H, H —CH₃ —CH₃ -φ H R, S 2,5-di-CH₃O-φ- H, H —CH₃ —CH₃ -φ HR, S 3,5-di-F-φ- H, H —CH₃ —CH₃ -φ H R, S 2-CH₃-φ- H, H —CH₃ —CH₃ -φ HR, S (φ)₂CH— H, H —CH₃ —CH₃ -φ H R, S φ-O—CH₂— H, H —CH₃ —CH₃ -φ H R, Sindol-3-yl- H, H —CH₃ —CH₃ -φ H R, S 4-CF₃-φ- H, H —CH₃ —CH₃ -φ H R, S4-CH₃-φ-O— H, H —CH₃ —CH₃ -φ H R, S 4-HOCH₂-φ-O— H, H —CH₃ —CH₃ -φ H R,S 2-(φ-O-)φ- H, H —CH₃ —CH₃ -φ H R, S 3-(φ-O-)φ- H, H —CH₃ —CH₃ -φ H R,S 3,4-di-Cl-φ-O— H, H —CH₃ —CH₃ -φ H R, S 4-F-φ-O— H, H —CH₃ —CH₃ -φ HR, S CH₃S— H, H —CH₃ —CH₃ -φ H R, S CH₃O— H, H —CH₃ —CH₃ -φ H R, S φ-O—H, H —CH₃ —CH₃ -φ H S φ- H, H —CH₃ —CH₃ -φ H S φ-CH₂CH₂— H, H —CH₃ —CH₃-φ H S 3-CH₃O-φ-O— H, H —CH₃ —CH₃ -φ H S 4-(n-C₄H₉O)φ-O— H, H —CH₃ —CH₃-φ H S 2-CH₃O-φ-CH₂— H, H —CH₃ —CH₃ -φ H S 4-F-φ- H, H —CH₃ —CH₃ -φ H S(CH₃)₂CH—O— H, H —CH₃ —CH₃ -φ H S 1-φ-tetrazol-5-yl H, H —CH₃ —CH₃ -φ HS 3-(3,4-merhylene- H, H —CH₃ —CH₃ -φ H S dioxy)φ-CH₂— cyclopentyl-CH₂—H, H —CH₃ —CH₃ -φ H S cyclopenten-2-yl- H, H —CH₃ —CH₃ -φ H S2-F-6-Cl-φ- H, H —CH₃ —CH₃ -φ H S cyclohexyl- H, H —CH₃ —CH₃ -φ H S2,5-di-F-φ- H, H —CH₃ —CH₃ -φ H S 2,3,4,5,6-penta-F-φ-O— H, H —CH₃ —CH₃-φ H S 3,5-di-CH₃-φ-O— H, H —CH₃ —CH₃ -φ H S 4-Cl-φ H, H —CH₃ —CH₃ -φ HS 3-Cl-φ-O— H, H —CH₃ —CH₃ -φ H S benzo[b]thiophen-3-yl H, H —CH₃ —CH₃-φ H S φ- ═O —CH₃ —CH₃ -φ H S 3,5-di-CH₃O-φ- H, H —CH₃ —CH₃ -φ H S2,5-di-CH₃-φ- H, H —CH₃ —CH₃ -φ H S 2,6-di-F-φ- H, H —CH₃ —CH₃ -φ H S2,4-di-F-φ- H, H —CH₃ —CH₃ -φ H S mesityl H, H —CH₃ —CH₃ -φ H S φ-φ- H,H —CH₃ —CH₃ -φ H S 3,4-di-F-φ- H, H —CH₃ —CH₃ -φ H S trans-styryl H, H—CH₃ —CH₃ -φ H S φ-C(O)CH₂— H, H —CH₃ —CH₃ -φ H S CH₃CH₂CH═CH— H, H —CH₃—CH₃ -φ H S (trans) CH₃CH₂CH₂CH₂CH₂— H, H —CH₃ —CH₃ -φ H S 4-CH₃-φ-CH₂—H, H —CH₃ —CH₃ -φ H S 4-Cl-φ-CH₂— H, H —CH₃ —CH₃ -φ H S CH₃CH(φ)— H, H—CH₃ —CH₃ -φ H S 4-CH₃O-φ-CH₂CH₂— H, H —CH₃ —CH₃ -φ H S CH₃OC(O)CH₂— H,H —CH₃ —CH₃ -φ H S φ-CH₂CH₂— H, H —CH₃ —CH₃ -φ H S φCH₂SCH₂— H, H —CH₃—CH₃ -φ H S CH₃CH₂CH(CH₃)— H, H —CH₃ —CH₃ -φ H S

H, H —CH₃ —CH₃ -φ H S indan-2-yl H, H —CH₃ —CH₃ -φ H S 4-CH₃O-φ- H, H—CH₃ —CH₃ -φ H S 2-Cl-φ-O— H, H —CH₃ —CH₃ -φ H S 2-thienyl H, H —CH₃—CH₃ -φ H S 2-CF₃-φ- H, H —CH₃ —CH₃ -φ H S 4-CH₃-φ- H, H —CH₃ —CH₃ -φ HS 2,6-di-F-φ- H, OH —CH₃ —CH₃ -φ H S 4-CH₃O-φ-CH₂— H, H —CH₃ —CH₃ -φ H S3,5-di-F-φ- H, H —CH₃ —CH₃ -φ H S 3-CH₃-φ- H, H —CH₃ —CH₃ -φ H S 3-F-φ-H, H —CH₃ —CH₃ -φ H S 4-Cl-φ-O— H, H —CH₃ —CH₃ -φ H S 2-naphthyl H, H—CH₃ —CH₃ -φ H S 3-Cl-φ- H, H —CH₃ —CH₃ -φ H S 3-CH₃-φ-O— H, H —CH₃ —CH₃-φ H S 3,4-methylenedioxy-φ- H, H —CH₃ —CH₃ -φ H S 2-CH₃O-φ-O— H, H —CH₃—CH₃ -φ H S 4-[(CH₃)₂CH]φ-O— H, H —CH₃ —CH₃ -φ H S 4-φ-O-φ- H, H —CH₃—CH₃ -φ H S φ-S— H, H —CH₃ —CH₃ -φ H S 4-CH₃CH₂O-φ- H, H —CH₃ —CH₃ -φ HS 2,5-di-CH₃O-φ- H, H —CH₃ —CH₃ -φ H S 2-CH₃-φ- H, H —CH₃ —CH₃ -φ H S(φ)₂CH— H, H —CH₃ —CH₃ -φ H S φ-O—CH₂— H, H —CH₃ —CH₃ -φ H S indol-3-yl-H, H —CH₃ —CH₃ -φ H S 4-CF₃-φ- H, H —CH₃ —CH₃ -φ H S 3,5-di-CF₃-φ- H, H—CH₃ —CH₃ -φ H S 2-(φ-O-)φ- H, H —CH₃ —CH₃ -φ H S 3-(φ-O-)φ- H, H —CH₃—CH₃ -φ H S 4-F-φ-O— H, H —CH₃ —CH₃ -φ H S 2,4-di-Cl-φ- H, H —CH₃ —CH₃-φ H S CHS₃— H, H —CH₃ —CH₃ -φ H S 4-F-φ- H, OH —CH₃ —CH₃ -φ H S4-thionaphthenyl H, H —CH₃ —CH₃ -φ H S CH₃O— H, H —CH₃ —CH₃ -φ H SCH₃CH₂O— H, H —CH₃ —CH₃ -φ H S 2-Cl-φ-CH₂— H, H —CH₃ —CH₃ -φ H S CH₃CH₂—H, H —CH₃ —CH₃ -φ H S CH₃CH₂CH₂CH₂— H, H —CH₃ —CH₃ -φ H S φCH₂CH₂CH₂— H,H —CH₃ —CH₃ -φ H S thien-2-yl-CH₂CH₂— H, H —CH₃ —CH₃ -φ H S3-CH₃O-φ-CH₂— H, H —CH₃ —CH₃ -φ H S (CH₃)₂CHCH₂CH₂— H, H —CH₃ —CH₃ -φ HS φ-CH₂— H, H —CH₃ —CH₃ -φ H S CH₃(CH₂)₅— H, H —CH₃ —CH₃ -φ H S3-HO-φ-CH₂— H, H —CH₃ —CH₃ -φ H S 4-HO-φ-CH₂— H, H —CH₃ —CH₃ -φ H S3,4,5-CF₃-φ- H, H —CH₃ —CH₃ -φ H S cyclopentyl H, H —CH₃ —CH₃ -φ H S

H, H —CH₃ —CH₃ -φ H S 2-CH₃-benzofuran-3-yl H, H —CH₃ —CH₃ -φ H S CH₃—H, H —CH₃ —CH₃ -φ H S cyclopropyl H, H —CH₃ —CH₃ -φ H S CH₃OCH₂— H, H—CH₃ —CH₃ -φ H S thienyl-CH₂CH₂CH₂— H, H —CH₃ —CH₃ -φ H S 4-F-φ-CH₂— H,H —CH₃ —CH₃ -φ H S 4-F-φ-O—CH₂— H, H —CH₃ —CH₃ -φ H S norbornan-2-yl H,H —CH₃ —CH₃ -φ H S 2,3-di-F-φ- H, OH —CH₃ —CH₃ -φ H S CH₃CH═CH— H, H—CH₃ —CH₃ -φ H S 2,4-di-Cl-φ-O— H, H —CH₃ —CH₃ -φ H S CH₂CH₂—2,3-di-Cl-φ-O— H, H —CH₃ —CH₃ -φ H S 2-F-φ- H, H —CH₃ —CH₃ -φ H S2-NO₂-φ- H, H —CH₃ —CH₃ -φ H S 4-HOCH₂-φ-O— H, H —CH₃ —CH₃ -φ H S2-F-3-CF₃-φ- H, H —CH₃ —CH₃ -φ H S 2,4,6-tri-CF₃-φ- H, H —CH₃ —CH₃ -φ HS 2-F-2-CF₃-φ H, H —CH₃ —CH₃ -φ H S CF₃CH₂— H, H —CH₃ —CH₃ -φ H S2-F-4-CF₃-φ- H, H —CH₃ —CH₃ -φ H S 4-Br-φ- H, H —CH₃ —CH₃ -φ H S4-F-φ-C(O)CH₂— H, H —CH₃ —CH₃ -φ H S 2-CH₃-φ-O— H, H —CH₃ —CH₃ -φ H S4-CH₃O-φ-O— H, H —CH₃ —CH₃ -φ H S φSO₂CH₂— H, H —CH₃ —CH₃ -φ H S2-CH₃O-φ- H, H —CH₃ —CH₃ -φ H S 2-Br-φ- H, H —CH₃ —CH₃ -φ H S4-[(CH₃)₂CH]φ- H, H —CH₃ —CH₃ -φ H S CH₂═CHCH₂— H, H —CH₃ —CH₃ -φ H S4-HO-φ-O— H, H —CH₃ —CH₃ -φ H S CH₃OCH₂— H, H —CH₃ —CH₃ -φ H S 2-HO-φ-H, H —CH₃ —CH₃ -φ H S 3,4-di-CH₃O-φ- H, H —CH₃ —CH₃ -φ H S4-CH₃O-φ-C(O)CH₂— H, H —CH₃ —CH₃ -φ H S thien-3-yl H, H —CH₃ —CH₃ -φ H SφCH₂CH₂CH₂CH₂— H, H —CH₃ —CH₃ -φ H S (CH₃)₂CH— H, H —CH₃ —CH₃ -φ H S2,3,5-tri-F-φ- H, H —CH₃ —CH₃ -φ H S 2,4,5-tri-F-φ- H, H —CH₃ —CH₃ -φ HS adamantan-1-yl H, H —CH₃ —CH₃ -φ H S cyclohexyl- H, H —CH₃ —CH₃ -φ H SCH₂CH₂CH₂— thien-2-yl H, H -φ —CH₃ -φ H S 3-CF₃-φ- H, H -φ —CH₃ -φ H S3,5-di-F-φ- H, H -φ —CH₃ -φ H S 3-CH₃-φ- H, H -φ —CH₃ -φ H S 3-F-φ- H, H-φ —CH₃ -φ H S 3-Br-φ- H, H -φ —CH₃ -φ H S 3-Cl-φ H, H -φ —CH₃ -φ H S3,4-methylenedioxy-φ- H, H -φ —CH₃ -φ H S φ-S— H, H -φ —CH₃ -φ H S3,5-di-CF₃-φ- H, H -φ —CH₃ -φ H S CH₃S— H, H -φ —CH₃ -φ H S φ-O— H, H -φ—CH₃ -φ H S φ- H, H -φ —CH₃ -φ H S cyclohexyl H, H -φ —CH₃ -φ H S2,5-di-F-φ- H, H -φ —CH₃ -φ H S benzo[b]thiophen-3-yl H, H -φ —CH₃ -φ HS φ- ═O -φ —CH₃ -φ H S 2,6-di-F-φ- H, H -φ —CH₃ -φ H S 2,4-di-F-φ- H, H-φ —CH₃ -φ H S 3,4-di-F-φ- H, H -φ —CH₃ -φ H S CH₃CH₂— H, H -φ —CH₃ -φ HS CH₃(CH₂)₄ H, H -φ —CH₃ -φ H S thien-2-yl-CH₂CH₂— H, H -φ —CH₃ -φ H S(CH₃)₂CHCH₂CH₂— H, H -φ —CH₃ -φ H S φCH₂— H, H -φ —CH₃ -φ H Scyclopentyl H, H -φ —CH₃ -φ H S CH₃— H, H -φ —CH₃ -φ H S 3,4,5-CF₃-φ- H,H -φ —CH₃ -φ H S φ-CH₂CH₂— H, H -φ —CH₃ -φ H S 2-thienyl H, H —CH₃—CH₂CH₂— -φ H R, S CH₂CF₃ 2-thienyl H, H —CH₃ —CH₂C(O)φ -φ H R, S2-thienyl H, H —CH₃ —CH₃ 2-thiazolyl H R, S 2-thienyl H, H —CH₃ —CH₃ -φCl R, S 2-thienyl H, H —CH₃ —CH₃ 2-Cl-φ Cl R, S 2-thienyl H, H —CH₃ —CH₃2-thienyl H R, S 2-thienyl H, H —CH₃ —CH₃ cyclohexyl H R, S 2-thienyl H,H —CH₃ —CH₃ -2-F-φ- Br R, S 3,5-di-F-φ- H, H —CH₃ —CH₂CH₂— -φ H R, SCH₂CF₃ 3,5-di-F-φ- H, H —CH₃ —CH₂C(O)φ -φ H R, S 3,5-di-F-φ- H, H —CH₃—CH₃ 2-thiazolyl H R, S 3,5-di-F-φ- H, H —CH₃ —CH₃ -φ Cl R, S3,5-di-F-φ- H, H —CH₃ —CH₃ 2-Cl-φ- Cl R, S 3,5-di-F-φ- H, H —CH₃ —CH₃thien-2-yl H R, S 3,5-di-F-φ- H, H —CH₃ —CH₃ -cyclohexyl H R, S3,5-di-F-φ- H, H —CH₃ —CH₃ 2-F-φ- Br R, S 3-F-φ- H, H —CH₃ —CH₂CH₂— -φ HR, S CH₂CF₃ 3-F-φ- H, H —CH₃ —CH₂C(O)φ -φ H R, S 3-F-φ- H, H —CH₃ —CH₃2-thiazolyl H R, S 3-F-φ- H, H —CH₃ —CH₃ -φ Cl R, S 3-F-φ- H, H —CH₃—CH₃ 2-Cl-φ- Cl R, S 3-F-φ- H, H —CH₃ —CH₃ thien-2-yl H R, S 3-F-φ- H, H—CH₃ —CH₃ cyclohexyl H R, S 3-F-φ- H, H —CH₃ —CH₃ 2-F-φ- Br R, S CH₃S—H, H —CH₃ —CH₂CH₂— -φ H R, S CH₂CF₃ CH₃S— H, H —CH₃ —CH₂C(O)φ -φ H R, SCH₃S— H, H —CH₃ —CH₃ 2-thiazolyl H R, S CH₃S— H, H —CH₃ —CH₃ -φ Cl R, SCH₃S— H, H —CH₃ —CH₃ 2-Cl-φ- Cl R, S CH₃S— H, H —CH₃ —CH₃ 2-thienyl H R,S CH₃S— H, H —CH₃ —CH₃ cyclohexyl H R, S CH₃S— H, H —CH₃ —CH₃ 2-F-φ- BrR, S φ- H, H —CH₃ —CH₂CH₂— -φ H R, S CH₂CF₃ φ- H, H —CH₃ —CH₂C(O)φ -φ HR, S φ- H, H —CH₃ —CH₃ 2-thiazolyl H R, S φ- H, H —CH₃ —CH₃ -φ Cl R, Sφ- H, H —CH₃ —CH₃ 2-Cl-φ- Cl R, S φ- H, H —CH₃ —CH₃ 2-thienyl H R, S φ-H, H —CH₃ —CH₃ cyclohexyl H R, S φ- ═O —CH₃ —CH₂CH₂— -φ H R, S CH₂CF₃ φ-═O —CH₃ —CH₂C(O)φ -φ H R, S φ- ═O —CH₃ —CH₃ 2-thiazolyl H R, S φ- ═O—CH₃ —CH₃ 2-Cl-φ- Cl R, S φ- ═O —CH₃ —CH₃ 2-thienyl H R, S φ- ═O —CH₃—CH₃ cyclohexyl H R, S φ- ═O —CH₃ —CH₃ 2-F-φ- Br R, S CH₃CH₂— H, H —CH₃—CH₂CH₂— -φ H R, S CH₂CF₃ CH₃CH₂— H, H —CH₃ —CH₂C(O)φ -φ H R, S CH₃CH₂—H, H —CH₃ —CH₃ 2-thiazolyl H R, S CH₃CH₂— H, H —CH₃ —CH₃ -φ Cl R, SCH₃CH₂— H, H —CH₃ —CH₃ 2-Cl-φ- Cl R, S CH₃CH₂— H, H —CH₃ —CH₃ 2-thienylH R, S CH₃CH₂— H, H —CH₃ —CH₃ cyclohexyl H R, S CH₃CH₂— H, H —CH₃ —CH₃2-F-φ- Br R, S (2-thienyl)-CH₂CH₂— H, H —CH₃ —CH₂CH₂— -φ H R, S CH₂CF₃(2-thienyl)-CH₂CH₂— H, H —CH₃ —CH₂C(O)φ -φ H R, S (2-thienyl)-CH₂CH₂— H,H —CH₃ —CH₃ 2-thiazolyl H R, S (2-thienyl)-CH₂CH₂— H, H —CH₃ —CH₃ -φ ClR, S (2-thienyl)-CH₂CH₂— H, H —CH₃ —CH₃ 2-Cl-φ- Cl R, S(2-thienyl)-CH₂CH₂— H, H —CH₃ —CH₃ 2-thienyl H R, S (2-thienyl)-CH₂CH₂—H, H —CH₃ —CH₃ cyclohexyl H R, S (2-thienyl)-CH₂CH₂— H, H —CH₃ —CH₃2-F-φ- Br R, S cyclopentyl H, H —CH₃ —CH₂CH₂— -φ H R, S CH₂CF₃cyclopentyl H, H —CH₃ —CH₂C(O)φ -φ H R, S cyclopentyl H, H —CH₃ —CH₃2-thiazolyl H R, S cyclopentyl H, H —CH₃ —CH₃ -φ Cl R, S cyclopentyl H,H —CH₃ —CH₃ 2-Cl-φ- Cl R, S cyclopentyl H, H —CH₃ —CH₃ 2-thienyl H R, Scyclopentyl H, H —CH₃ —CH₃ cyclohexyl H R, S cyclopentyl H, H —CH₃ —CH₃2-F-φ- Br R, S

H, H —CH₃ —CH₂CH₂—CH₂CF₃ -φ H R, S

H, H —CH₃ —CH₂C(O)φ -φ H R, S

H, H —CH₃ —CH₃ 2-thiazolyl H R, S

H, H —CH₃ —CH₃ -φ Cl R, S

H, H —CH₃ —CH₃ 2-Cl-φ- Cl R, S

H, H —CH₃ —CH₃ 2-thienyl H R, S

H, H —CH₃ —CH₃ cyclohexyl H R, S

H, H —CH₃ —CH₃ 2-F-φ- Br R, S CH₃CH₂— H, H —CH₃ —CH₂CH₂— -φ H R, SCH₂CF₃ CF₃CH₂— H, H —CH₃ —CH₂C(O)φ -φ H R, S CF₃CH₂— H, H —CH₃ —CH₃2-thiazolyl H R, S CF₃CH₂— H, H —CH₃ —CH₃ -φ Cl R, S CF₃CH₂— H, H —CH₃—CH₃ 2-Cl-φ- Cl R, S CF₃CH₂— H, H —CH₃ —CH₃ 2-thienyl H R, S CF₃CH₂— H,H —CH₃ —CH₃ cyclohexyl H R, S CF₃CH₂— H, H —CH₃ —CH₃ 2-F-φ- Br R, S(CH₃)₂CH— H, H —CH₃ —CH₂CH₂— -φ H R, S CH₂CF₃ (CH₃)₂CH— H, H —CH₃—CH₂C(O)φ -φ H R, S (CH₃)₂CH— H, H —CH₃ —CH₃ 2-thiazolyl H R, S(CH₃)₂CH— H, H —CH₃ —CH₃ -φ Cl R, S (CH₃)₂CH— H, H —CH₃ —CH₃ 2-Cl-φ- ClR, S (CH₃)₂CH— H, H —CH₃ —CH₃ 2-thienyl H R, S (CH₃)₂CH— H, H —CH₃ —CH₃cyclohexyl H R, S (CH₃)₂CH— H, H —CH₃ —CH₃ 2-F-φ- Br R, S (CH₃)₂CHCH₂—H, OH —CH₃ —CH₂CH₂— -φ H R, S CH₂CF₃ (CH₃)₂CHCH₂— H, OH —CH₃ —CH₂C(O)φ-φ H R, S (CH₃)₂CHCH₂— H, OH —CH₃ —CH₃ 2-thiazolyl H R, S (CH₃)₂CHCH₂—H, OH —CH₃ —CH₃ -φ Cl R, S (CH₃)₂CHCH₂— H, OH —CH₃ —CH₃ 2-Cl-φ- Cl R, S(CH₃)₂CHCH₂— H, OH —CH₃ —CH₃ 2-thienyl H R, S (CH₃)₂CHCH₂— H, OH —CH₃—CH₃ cyclohexyl H R, S (CH₃)₂CHCH₂— H, OH —CH₃ —CH₃ 2-F-φ- Br R, S -φ H,OH —CH₃ —CH₂CH₂— -φ H R, S CH₂CF₃ -φ H, OH —CH₃ —CH₂C(O)φ -φ H R, S -φH, OH —CH₃ —CH₃ 2-thiazolyl H R, S -φ H, OH —CH₃ —CH₃ -φ Cl R, S -φ H,OH —CH₃ —CH₃ 2-Cl-φ- Cl R, S -φ H, OH —CH₃ —CH₃ 2-thienyl H R, S -φ H,OH —CH₃ —CH₃ cyclohexyl H R, S -φ H, OH —CH₃ —CH₃ 2-F-φ- Br R, S3,5-di-F-φ- H, H —CH₃ 3-F-φ- -φ H R, S 3,5-di-F-φ- H, H —CH₃ —CH₂φ -φ HR, S 3,5-di-F-φ- H, H —CH₃ 4-t-butyl- -φ H R, S CH₂φ 3,5-di-F-φ- H, H—CH₃ —CH₂CH₂— -φ H R, S cyclohexyl 3,5-di-F-φ- H, H —CH₃ 3,3-dimethyl--φ H R, S butyl 3,5-di-F-φ- H, H —CH₃ CH₃OC(O)— -φ H R, S CH(φ)-3,5-di-F-φ- H, H —CH₃ 2-ethyl- -φ H R, S butyl 3,5-di-F-φ- H, H —CH₃cyclohexyl- -φ H R, S methyl 3,5-di-F-φ- H, H —CH₃ 2-φ-ethyl- -φ H R, S3,5-di-F-φ- H, H —CH₃ 3-φ-propyl- -φ H R, S 3,5-di-F-φ- H, H —CH₃ 2-(N--φ H R, S phthalimidyl) ethyl) 3,5-di-F-φ- H, H —CH₃ 2-biphenyl- -φ H R,S methyl 3,5-di-F-φ- H, H —CH₃ 2-tetrahydro- -φ H R, S turanyl- methyl3,5-di-F-φ- H, H —CH₃ 2-(1,4-benzo- -φ H R, S dioxanyl) methyl3,5-di-F-φ- H, H —CH₃ 3-(5-chloro- -φ H R, S benzo[b]thien -yl)methyl3,5-di-F-φ- H, H —CH₃ 3,3-dimethyl- -φ H R, S 2-oxo-propyl 3,5-di-F-φ-H, H —CH₃ 5-benzofuraz- -φ H R, S anylmethyl 3,5-di-F-φ- H, H —CH₃3-(φ-O)- -φ H R, S propyl 3,5-di-F-φ- H, H —CH₃ 6-(2-CF₃- -φ H R, Squinolinyl) methyl 3,5-di-F-φ- H, H —CH₃ 2-methylbutyl -φ H R, S3,5-di-F-φ- H, H —CH₃ ethyl -φ H R, S 3,5-di-F-φ- H, H —CH₃ 3-pyridyl--φ H R, S methyl 3,5-di-F-φ- H, H —CH₃ 2-oxo-2-(N- -φ H R, S indolinyl)-ethyl) 3,5-di-F-φ- H, H —CH₃ 4-(3,5-di- -φ H R, S methyl- isoxazolyl)methyl) 3,5-di-F-φ- H, H —CH₃ 2-CH₃O-ethyl -φ H R, S cyclopentyl H, H—CH₃ —CH₂φ -φ H R, S cyclopentyl H, H —CH₃ (4-t-butyl-) -φ H R, S CH₂φcyclopentyl H, H —CH₃ —CH₂CH₂— -φ H R, S cyclohexyl cyclopentyl H, H—CH₃ 3,3-dimethyl- -φ H R, S butyl cyclopentyl H, H —CH₃ isopropyl -φ HR, S cyclopentyl H, H —CH₃ CH₃OC(O)— -φ H R, S CH(φ)- cyclopentyl H, H—CH₃ 2-ethyl- -φ H R, S butyl cyclopentyl H, H —CH₃ cyclohexyl- -φ H R,S methyl cyclopentyl H, H —CH₃ 2-φ-ethyl- -φ H R, S cyclopentyl H, H—CH₃ 3-φ-propyl- -φ H R, S cyclopentyl H, H —CH₃ 2-(N- -φ H R, Sphthalimidyl) ethyl) cyclopentyl H, H —CH₃ 2-biphenyl- -φ H R, S methylcyclopentyl H, H —CH₃ 3-(5-chloro- -φ H R, S benzo[b]thien -yl)methylcyclopentyl H, H —CH₃ 3,3-dimethyl- -φ H R, S 2-oxo-butyl cyclopentyl H,H —CH₃ 5-benzofuraz- -φ H R, S anylmethyl cyclopentyl H, H —CH₃ 3-(φ-O)--φ H R, S propyl cyclopentyl H, H —CH₃ 6-(2-CF₃- -φ H R, S quinolinyl)methyl cyclopentyl H, H —CH₃ cyclopropyl- -φ H R, S methyl cyclopentylH, H —CH₃ 2-methyl- -φ H R, S butyl cyclopentyl H, H —CH₃ ethyl -φ H R,S cyclopentyl H, H —CH₃ 4-(3,5-di- -φ H R, S methyl- isoxazolyl) methyl)cyclopentyl H, H —CH₃ propyl -φ H R, S cyclopentyl H, H —CH₃2-CH₃O-ethyl -φ H R, S CF₃CH₂— H, H —CH₃ —CH₂φ -φ H R, S CF₃CH₂— H, H—CH₃ (4-t-butyl)- -φ H R, S CH₂φ CF₃CH₂— H, H —CH₃ —CH₂CH₂— -φ H R, Scyclohexyl CF₃CH₂— H, H —CH₃ 3,3-dimethyl- -φ H R, S butyl CF₃CH₂— H, H—CH₃ isopropyl -φ H R, S CF₃CH₂— H, H —CH₃ CH₃OC(O)— -φ H R, S CH(φ)—CF₃CH₂— H, H —CH₃ 2-ethyl- -φ H R, S butyl CF₃CH₂— H, H —CH₃ cyclohexyl--φ H R, S methyl CF₃CH₂— H, H —CH₃ 3-φ-propyl- -φ H R, S CF₃CH₂— H, H—CH₃ 2-biphenyl- -φ H R, S methyl CF₃CH₂— H, H —CH₃ 3-(5-chloro- -φ H R,S benzo[b]thien -yl)methyl CF₃CH₂— H, H —CH₃ 3,3-dimethyl- -φ H R, S2-oxo-butyl CF₃CH₂— H, H —CH₃ 5-benzofuraz- -φ H R, S anylmethyl CF₃CH₂—H, H —CH₃ 3-(φ-O)- -φ H R, S propyl CF₃CH₂— H, H —CH₃ 6-(2-CF₃- -φ H R,S quinolinyl) methyl CF₃CH₂— H, H —CH₃ cyclopropyl- -φ H R, S methylCF₃CH₂— H, H —CH₃ 2-methyl- -φ H R, S butyl CF₃CH₂— H, H —CH₃ ethyl -φ HR, S CF₃CH₂— H, H —CH₃ 4-(3,5-di- -φ H R, S methyl- isoxazolyl) methylCF₃CH₂— H, H —CH₃ propyl -φ H R, S CF₃CH₂— H, H —CH₃ 2-CH₃O-ethyl -φ HR, S N-pyrrolidinyl H, H —CH₃ —CH₃ -φ H R, S 2-Cl-φ-O— H, H —CH₃ —CH₃ -φH R, S 2-thienyl H, H —CH₃ —CH₃ -φ H R, S 3-CF₃-φ- H, H —CH₃ —CH₃ -φ HR, S 4-CH₃-φ- H, H —CH₃ —CH₃ -φ H R, S 4-CH₃O-φ-CH₂— H, H —CH₃ —CH₃ -φ HR, S 3,5-di-F-φ- H, H —CH₃ —CH₃ -φ H R, S 3-CH₃-φ- H, H —CH₃ —CH₃ -φ HR, S 3-F-φ- H, H —CH₃ —CH₃ -φ H R, S 3-Br-φ- H, H —CH₃ —CH₃ -φ H R, S4-Cl-O-φ- H, H —CH₃ —CH₃ -φ H R, S 2-naphthyl H, H —CH₃ —CH₃ -φ H R, S3-CH₃-φ-O— H, H —CH₃ —CH₃ -φ H R, S

[1326] TABLE 8C-2

R² = 1 position; R³ = 5 position; R⁴ = 7 position Iso. R X/X′ R¹ R² R³R⁴ (at *) 2-thienyl H,H —CH₃ 2,2-di-CH₃- 2,2-di- H R,S propyl CH₃-propyl3,5-di-F-φ H,H —CH₃ 2,2-di-CH₃- 2,2-di- H R,S propyl CH₃-propyl 3-F-φH,H —CH₃ 2,2-di-CH₃- 2,2-di- H R,S propyl CH₃-propyl CH₃S— H,H —CH₃2,2-di-CH₃- 2,2-di- H R,S propyl CH₃-propyl φ- H,H —CH₃ 2,2-di-CH₃-2,2-di- H R,S propyl CH₃-propyl φ- ═O —CH₃ 2,2-di-CH₃- 2,2-di- H R,Spropyl CH₃-propyl CH₃CH₂— H,H —CH₃ 2,2-di-CH₃- 2,2-di- H R,S propylCH₃-propyl 2-thienyl- H,H —CH₃ 2,2-di-CH₃- 2,2-di- H R,S CH₃CH₂— propylCH₃-propyl cyclopentyl H,H —CH₃ 2,2-di-CH₃- 2,2-di- H R,S propylCH₃-propyl

H,H —CH₃ R,S 2,2-di-CH₃- propyl R,S 2,2-di- CH₃-propyl H R,S CF₃CH₂— H,H—CH₃ 2,2-di-CH₃- 2,2-di- H R,S propyl CH₃-propyl (CH₃)₂CH— H,H —CH₃2,2-di-CH₃- 2,2-di- H R,S propyl CH₃-propyl (CH₃)₂CH— OH,H —CH₃2,2-di-CH₃- 2,2-di- H R,S propyl CH₃-propyl φ- OH,H —CH₃ 2,2-di-CH₃-2,2-di- H R,S propyl CH₃-propyl

[1327] Also included within the scope of this invention are prodrugs ofthe compounds of formula I above including acylated forms of alcoholsand thiols, aminals of one or more amines, and the like.

DETAILED DESCRIPTION OF THE INVENTION

[1328] As above, this invention relates to compounds which inhibitβ-amyloid peptide release and/or its synthesis, and, accordingly, haveutility in treating Alzheimer's disease. However, prior to describingthis invention in further detail, the following terms will first bedefined.

Definitions

[1329] The term “β-amyloid peptide” refers to a 3943 amino acid peptidehaving a molecular weight of about 4.2 kD, which peptide issubstantially homologous to the form of the protein described byGlenner, et al.¹ including mutations and post-translationalmodifications of the normal β-amyloid peptide. In whatever form, theβ-amyloid peptide is an approximate 39-43 amino acid fragment of a largemembrane-spanning glycoprotein, referred to as the β-amyloid precursorprotein (APP). Its 43-amino acid sequence is: 1 Asp Ala Glu Phe Arg HisAsp Ser Gly Tyr (SEQ ID NO: 1) 11 Glu Val His His Gln Lys Leu Val PhePhe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu MetVal Gly Gly Val Val 41 Ile Ala Thr

[1330] or a sequence which is substantially homologous thereto. “Alkyl”refers to monovalent alkyl groups preferably having from 1 to 10 carbonatoms and more preferably 1 to 6 carbon atoms. This term is exemplifiedby groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, n-hexyl, and the like.

[1331] “Substituted alkyl” refers to an alkyl group, preferably of from1 to 10 carbon atoms, having from 1 to 5 substituents, and preferably 1to 3 substituents, selected from the group consisting of alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl,aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol,thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-substituted alkyl, —SO-aryl, -SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, -SO₂-heteroaryl, and mono- anddi-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclicamino, and unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl, aryl, heteroaryland heterocyclic.

[1332] “Alkylene” refers to divalent alkylene groups preferably havingfrom 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Thisterm is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—)and the like.

[1333] “Substituted alkylene” refers to an alkylene group, preferably offrom 1 to 10 carbon atoms, having from 1 to 3 substituents selected fromthe group consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl,carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy,aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino,mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- anddi-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetricdi-substituted amines having different substituents selected from alkyl,substituted alkyl, aryl, heteroaryl and heterocyclic. Additionally, suchsubstituted alkylene groups include those where 2 substituents on thealkylene group are fused to form one or more cycloalkyl, aryl,heterocyclic or heteroaryl groups fused to the alkylene group.Preferably such fused cycloalkyl groups contain from 1 to 3 fused ringstructures.

[1334] “Alkenylene” refers to divalent alkenylene groups preferablyhaving from 2 to 10 carbon atoms and more preferably 2 to 6 carbonatoms. This term is exemplified by groups such as ethenylene (—CH═CH—),the propenylene isomers (e.g., —CH₂CH═CH— and —C(CH₃)═CH—) and the like.

[1335] “Substituted alkenylene” refers to an alkenylene group,preferably of from 2 to 10 carbon atoms, having from 1 to 3 substituentsselected from the group consisting of alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen,hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substitutedthioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- anddi-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclicamino, and unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl, aryl, heteroaryland heterocyclic. Additionally, such substituted alkylene groups includethose where 2 substituents on the alkylene group are fused to form oneor more cycloalkyl, aryl, heterocyclic or heteroaryl groups fused to thealkylene group.

[1336] “Alkaryl” refers to -alkylene-aryl groups preferably having from1 to 8 carbon atoms in the alkylene moiety and from 6 to 10 carbon atomsin the aryl moiety. Such alkaryl groups are exemplified by benzyl,phenethyl and the like.

[1337] “Alkoxy” refers to the group “alkyl-O—”. Preferred alkoxy groupsinclude, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

[1338] “Substituted alkoxy” refers to the group “substituted alkyl-O—”where substituted alkyl is as defined above.

[1339] “Alkylalkoxy” refers to the group “-alkylene-O-alkyl” whichincludes by way of example, methylenemethoxy (—CH₂OCH₃), ethylenemethoxy(—CH₂CH₂OCH₃), n-propylene-iso-propoxy (—CH₂CH₂CH₂OCH(CH₃)₂),methylene-t-butoxy (—CH₂—O—C(CH₃)₃) and the like.

[1340] “Alkylthioalkoxy” refers to the group “-alkylene-5-alkyl” whichincludes by way of example, methylenethiomethoxy (—CH₂SCH₃),ethylenethiomethoxy (—CH₂CH₂SCH₃), n-propylene-thio-iso-propoxy(—CH₂CH₂CH₂SCH(CH₃)₂), methylenethio-t-butoxy (—CH₂SC(CH₃)₃) and thelike.

[1341] “Alkenyl” refers to alkenyl groups preferably having from 2 to 10carbon atoms and more preferably 2 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkenyl unsaturation. Preferredalkenyl groups include ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂),iso-propenyl (—C(CH₃)═CH₂), and the like.

[1342] “Substituted alkenyl” refers to an alkenyl group as defined abovehaving from 1 to 3 substituents selected from the group consisting ofalkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl,aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol,thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl, andmono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono-and di-arylamino, mono- and di-heteroarylamino, mono- anddi-heterocyclic amino, and unsymmetric di-substituted amines havingdifferent substituents selected from alkyl, substituted alkyl, aryl,heteroaryl and heterocyclic.

[1343] “Alkynyl” refers to alkynyl groups preferably having from 2 to 10carbon atoms and more preferably 2 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkynyl unsaturation. Preferredalkynyl groups include ethynyl (—CH≡CH₂), propargyl (—CH₂C≡—CH) and thelike.

[1344] “Substituted alkynyl” refers to an alkynyl group as defined abovehaving from 1 to 3 substituents selected from the group consisting ofalkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl,aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol,thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl, andmono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono-and di-arylamino, mono- and di-heteroarylamino, mono- anddi-heterocyclic amino, and unsymmetric di-substituted amines havingdifferent substituents selected from alkyl, substituted alkyl, aryl,heteroaryl and heterocyclic.

[1345] “Acyl” refers to the groups alkyl-C(O)—, substituted alkyl-C(O)—,cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclicare as defined herein.

[1346] “Acylamino” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

[1347] “Aminoacyl” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

[1348] “Aminoacyloxy” refers to the group —NRC(O)OR where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

[1349] “Acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, aryl-C(O)O—, heteroaryl-C(O)O—, andheterocyclic-C(O)O— wherein alkyl, substituted alkyl, cycloalkyl, aryl,heteroaryl, and heterocyclic are as defined herein.

[1350] “Aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 14 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferredaryls include phenyl, naphthyl and the like.

[1351] Unless otherwise constrained by the definition for the arylsubstituent, such aryl groups can optionally be substituted with from 1to 5 substituents selected from the group consisting of acyloxy, 1 to 5and preferably 1 to 3 substituents selected from the group consisting ofhydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl, amino,aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, heterocyclic,aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy,thioaryloxy, thioheteroaryloxy, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl,—SO₂-heteroaryl, trihalomethyl, mono- and di-alkylamino, mono- anddi-(substituted alkyl)amino, mono- and di-arylamino, mono- anddi-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetricdi-substituted amines having different substituents selected from alkyl,substituted alkyl, aryl, heteroaryl and heterocyclic, and the like.Preferred substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy.

[1352] “Aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above including optionally substituted aryl groups as alsodefined above.

[1353] “Carboxyalkyl” refers to the group “—C(O)Oalkyl” where alkyl isas defined above.

[1354] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 12 carbonatoms having a single cyclic ring or multiple condensed rings. Suchcycloalkyl groups include, by way of example, single ring structuressuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like,or multiple ring structures such as adamantanyl, and the like.

[1355] “Substituted cycloalkyl” refers to cycloalkyl groups having from1 to 5 (preferably 1 to 3) substituents selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like.

[1356] “Cycloalkenyl” refers to cyclic alkenyl groups of from 4 to 8carbon atoms having a single cyclic ring and at least one point ofinternal unsaturation. Examples of suitable cycloalkenyl groups include,for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and thelike.

[1357] “Substituted cycloalkenyl” refers to cycloalkenyl groups havingfrom 1 to 5 substituents selected from the group consisting of hydroxy,acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino,aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo,nitro, heteroaryl, thioalkoxy, substituted thioalkoxy, trihalomethyl andthe like.

[1358] “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either fluoro or chloro.

[1359] “Heteroaryl” refers to an aromatic carbocyclic group of from 1 to15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogenand sulfur within at least one ring (if there is more than one ring).

[1360] Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents selected from the group consisting of alkyl,substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy, halo,nitro, heteroaryl, thiol, thioalkoxy, substituted thioalkoxy,thioaryloxy, trihalomethyl and the like. Such heteroaryl groups can havea single ring (e.g., pyridyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl). Preferred heteroaryls includepyridyl, pyrrolyl and furyl.

[1361] “Heterocycle” or “heterocyclic” refers to a monovalent saturatedor unsaturated group having a single ring or multiple condensed rings,from 1 to 15 carbon atoms and from 1 to 4 hetero atoms selected fromnitrogen, sulfur or oxygen within the ring.

[1362] Unless otherwise constrained by the definition for theheterocyclic substituent, such heterocyclic groups can be optionallysubstituted with 1 to 5 substituents selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, aryloxy,halo, nitro, heteroaryl, thiol, thioalkoxy, substituted thioalkoxy,thioaryloxy, trihalomethyl, and the like. Such heterocyclic groups canhave a single ring or multiple condensed rings. Preferred heterocyclicsinclude morpholino, piperidinyl, and the like.

[1363] Examples of nitrogen heterocycles and heteroaryls include, butare not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

[1364] “Oxyacylamino” refers to the group —OC(O)NRR where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

[1365] “Thiol” refers to the group —SH.

[1366] “Thioalkoxy” refers to the group —S-alkyl.

[1367] “Substituted thioalkoxy” refers to the group -S-substitutedalkyl.

[1368] “Thioaryloxy” refers to the group aryl-S— wherein the aryl groupis as defined above including optionally substituted aryl groups alsodefined above.

[1369] “Thioheteroaryloxy” refers to the group heteroaryl-S— wherein theheteroaryl group is as defined above including optionally substitutedaryl groups as also defined above.

[1370] As to any of the above groups which contain 1 or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible.

[1371] “Pharmaceutically acceptable salt” refers to pharmaceuticallyacceptable salts of a compound of Formula I which salts are derived froma variety of organic and inorganic counter ions well known in the artand include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate and the like can be used as the pharmaceuticallyacceptable salt.

[1372] The term “protecting group” or “blocking group” refers to anygroup which when bound to one or more hydroxyl, amino or carboxyl groupsof the compounds (including intermediates thereof such as theaminolactams, aminolactones, etc.) prevents reactions from occurring atthese groups and which protecting group can be removed by conventionalchemical or enzymatic steps to reestablish the hydroxyl, amino orcarboxyl group. The particular removable blocking group employed is notcritical and preferred removable hydroxyl blocking groups includeconventional substituents such as allyl, benzyl, acetyl, chloroacetyl,thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any othergroup that can be introduced chemically onto a hydroxyl functionalityand later selectively removed either by chemical or enzymatic methods inmild conditions compatible with the nature of the product.

[1373] Preferred removable amino blocking groups include conventionalsubstituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ),and the like which can be removed by conventional conditions compatiblewith the nature of the product.

[1374] Preferred carboxyl protecting groups include esters such asmethyl, ethyl, propyl, t-butyl etc. which can be removed by mildhydrolysis conditions compatible with the nature of the product.

Compound Preparation

[1375] When n is one or two, the compounds of formula I are readilyprepared by conventional amidation of a carboxyl acid as shown inreaction (1) below where, for the sake of illustration, n is one:

[1376] wherein R¹, R², W, X, Z and m are as defined above. The reactionis conventionally conducted by using at least a stoichiometric amount ofcarboxylic acid 1 and amine 2. This reaction is conventionally conductedfor peptide synthesis and synthetic methods used therein can also beemployed to prepare compound 3 which is a compound of formula I above.For example, well known coupling reagents such as carbodiimides with orwithout the use of well known additives such as N-hydroxysuccinimide,1-hydroxybenzotriazole, etc. can be used to facilitate coupling. Thereaction is conventionally conducted in an inert aprotic polar diluentsuch as dimethylformamide, dichloromethane, chloroform, acetonitrile,tetrahydrofuran and the like. Alternatively, the acid halide of compound1 can be employed in reaction (1) and, when so employed, it is typicallyemployed in the presence of a suitable base to scavenge the acidgenerated during the reaction. Suitable bases include, by way ofexample, triethylamine, diisopropylethylamine, N-methylmorpholine andthe like.

[1377] When n is zero, the compounds of formula I can be prepared byN-substitution reactions of compound 2. For example, when m=0 and n=0,N-arylation reactions on compound 2 lead to compounds of formula I. Whenm=1 and n=0, ) reaction of compound 2 with an acetic acid derivativerepresented by the formula R¹—T—CH₂—COOH also lead to compounds offormula I. Both reactions are described below.

Synthesis of Carboxylic Acid Starting Materials

[1378] Carboxylic acids 1 can be prepared by several divergent syntheticroutes with the particular route selected relative to the ease ofcompound preparation, commercial availability of starting materials,whether m is zero or one, whether n is one or two, etc.

[1379] A. Synthesis of Carboxylic Acids

[1380] When m is zero and n is one, a first synthetic method involvesthe introduction of the R¹ group to the amino acid NH₂CH(R²)COOH orester thereof.

[1381] The introduction of the R¹ group onto the amino acidNH₂CH(R²)COOH or ester thereof can be accomplished in several methods.For example, conventional coupling of a halo acetic acid with a primaryamine forms an amino acid as shown in reaction (2) below:

[1382] wherein R¹ and R² are as defined above and Z′ is a halo groupsuch as chloro or bromo. Alternatively, leaving groups other than halomay be employed such as triflate and the like. Additionally, suitableesters of 4 may be employed in this reaction.

[1383] As above, reaction (2) involves coupling of a suitable haloaceticacid derivative 4 with a primary amine 5 under conditions which providefor amino acid 6. This reaction is described by, for example, Yates, etal.¹⁴ and proceeds by combining approximately stoichiometric equivalentsof haloacetic acid 4 with primary amine 5 in a suitable inert diluentsuch as water, dimethylsulfoxide (DMSO) and the like. The reactionemploys an excess of a suitable base such as sodium bicarbonate, sodiumhydroxide, etc. to scavenge the acid generated by the reaction. Thereaction is preferably conducted at from about 25° C. to about 100° C.until reaction completion which typically occurs within 1 to about 24hours. This reaction is further described in U.S. Pat. No. 3,598,859,which is incorporated herein by reference in its entirety. Upon reactioncompletion, N-substituted amino acid 6 is recovered by conventionalmethods including precipitation, chromatography, filtration and thelike.

[1384] In reaction (2), each of the reagents (haloacetic acid 4, primaryamine 5 and alcohol 6 are well known in the art with a plurality of eachbeing commercially available.

[1385] In an alternative embodiment, the R¹ group can be coupled to analanine ester (or other suitable amino acid ester) by conventionalN-arylation. For example, a stoichiometric equivalent or slight excessof the amino acid ester can be dissolved in a suitable diluent such asDMSO and coupled with a halo-R¹ compound, Z′—R¹ where Z′ is a halo groupsuch as chloro or bromo and R¹ is as defined above. The reaction isconducted in the presence of an excess of base such as sodium hydroxideto scavenge the acid generated by the reaction. The reaction typicallyproceeds at from 15° C. to about 250° C. and is complete in about 1 to24 hours. Upon reaction completion, N-substituted amino acid ester isrecovered by conventional methods including chromatography, filtrationand the like. This ester is then hydrolyzed by conventional methods toprovide for carboxylic acid 1 for use in reaction (1).

[1386] In still another alternative embodiment, the esterified aminoacids of formula I above can be prepared by reductive amination of asuitable pyruvate ester in the manner illustrated in reaction (3) below:

[1387] wherein R is typically an alkyl group and R¹ and R² are asdefined above.

[1388] In reaction (3), approximately stoichiometric equivalents ofpyruvate ester 7 and amine 5 are combined in an inert diluent such asmethanol, ethanol and the like and the reaction solution treated underconditions which provide for imine formation (not shown). The imineformed is then reduced under conventional conditions by a suitablereducing agent such as sodium cyanoborohydride, H₂/palladium on carbonand the like to form the /N-substituted amino acid ester 8. In aparticularly preferred embodiment, the reducing agent is H₂/palladium oncarbon which is incorporated into the initial reaction medium whichpermits imine reduction in situ in a one pot procedure to provide forthe N-substituted amino acid ester 8.

[1389] The reaction is preferably conducted at from about 20° C. toabout 80° C. at a pressure of from 1 to 10 atmospheres until reactioncompletion which typically occurs within 1 to about 24 hours. Uponreaction completion, N-substituted amino acid ester 8 is recovered byconventional methods including chromatography, filtration and the like.

[1390] Subsequent hydrolysis of the ester 8 leads to the correspondingcarboxylic acid derivative 1 which can be employed in reaction (1)above.

[1391] For compounds where m is zero and n is two, conventional couplingof a second amino acid (e.g., NH₂CH(R²)C(O)OR where R is typically analkyl group) to the amino acid produced above (i.e., R¹NHCH(R²)COOH)provides for esters of an analogue of carboxylic acid 1 which are thenconventionally de-esterified to provide for an analogue of compound 1.

[1392] Alternatively, an ester such as H₂NCH(R²)C(O)NHCH(R²)COOR whereeach R² is independently as defined above and R is typically an alkylgroup can first be formed by conventional peptide synthetic procedures,N-substitution can be conducted in the manner described above followedby de-esterification to provide for analogues of carboxylic acids 1where n is two.

[1393] When m is one and n is one, a first synthetic method involvesconventional coupling of an acetic acid derivative with a primary amineof an esterified amino acid as shown in reaction (4) below:

[1394] wherein R is typically an alkyl group and R¹, R², X′ and X″ areas defined above.

[1395] Reaction (4) merely involves coupling of a suitable acetic acidderivative 9 with the primary amine of amino acid ester 10 underconditions which provide for the N-acetyl derivative 11. This reactionis conventionally conducted for peptide synthesis and synthetic methodsused therein can also be employed to prepare the N-acetyl amino acidesters 11 of this invention. For example, well known coupling reagentssuch as carbodiimides with or without the use of well known additivessuch as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be usedto facilitate coupling. The reaction is conventionally conducted in aninert aprotic polar diluent such as dimethylformamide, dichloromethane,chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively,the acid halide of compound 9 can be employed in reaction (4) and, whenso employed, it is typically employed in the presence of a suitable baseto scavenge the acid generated during the reaction. Suitable basesinclude, by way of example, triethylamine, diisopropylethylamine,N-methylmorpholine and the like.

[1396] Reaction (4) is preferably conducted at from about 0° C. to about60° C. until reaction completion which typically occurs within 1 toabout 24 hours. Upon reaction completion, N-acetyl amino acid ester 11is recovered by conventional methods including precipitation,chromatography, filtration and the like or alternatively is hydrolyzedto the corresponding acid without purification and/or isolation otherthan conventional work-up (e.g., aqueous extraction, etc.).

[1397] In reaction (4), each of the reagents (acetic acid derivative 9and amino acid ester 10) are well known in the art with a plurality ofeach being commercially available.

[1398] When m is one and n is two, a further amino acid ester is coupledto the amino acid ester 11 by first de-esterifying 11 and then usingwell known peptide coupling chemistry with well known coupling reagentssuch as carbodiimides with or without the use of well known additivessuch as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. which can beused to facilitate coupling. The reaction is conventionally conducted inan inert aprotic polar diluent such as dimethylfornamide,dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.De-esterification of the resulting ester provides for carboxylic acids 1having n equal to 2.

[1399] Alternatively, carboxylic acids 1 having n equal to 2 can beprepared by first forming the ester, N-acetylating these esters and thende-esterifying the resulting product.

[1400] Carboxylic acids 1 having m equal to 1 and n equal to 1 or 2 canalso be prepared by use of polymer supported forms of carbodiimidepeptide coupling reagents. A polymer supported form of EDC, for example,has been described (Tetrahedron Letters, 34(48), 7685 (1993))¹⁰.Additionally, a new carbodiimide coupling reagent, PEPC, and itscorresponding polymer supported forms have been discovered and are veryuseful for the preparation of such compounds.

[1401] Polymers suitable for use in making a polymer supported couplingreagent are either commercially available or may be prepared by methodswell known to the artisan skilled in the polymer arts. A suitablepolymer must possess pendant sidechains bearing moieties reactive withthe terminal amine of the carbodiimide. Such reactive moieties includechloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moietyis a chloromethyl group. Additionally, the polymer's backbone must beinert to both the carbodiimide and reaction conditions under which theultimate polymer bound coupling reagents will be used.

[1402] Certain hydroxymethylated resins may be converted intochloromethylated resins useful for the preparation of polymer supportedcoupling reagents. Examples of these hydroxylated resins include the4-hydroxymethylphenylacetamidomethyl resin (Pam Resin) and4-benzyloxybenzyl alcohol resin (Wang Resin) available from AdvancedChemtech of Louisville, Ky., USA (see Advanced Chemtech 1993-1994catalog, page 115). The hydroxymethyl groups of these resins may beconverted into the desired chloromethyl groups by any of a number ofmethods well known to the skilled artisan.

[1403] Preferred resins are the chloromethylated styrene/divinylbenzeneresins because of their ready commercial availability. As the namesuggests, these resins are already chloromethylated and require nochemical modification prior to use. These resins are commercially knownas Merrifield's resins and are available from Aldrich Chemical Companyof Milwaukee, Wis., USA (see Aldrich 1994-1995 catalog, page 899).Methods for the preparation of PEPC and its polymer supported forms areoutlined in the following scheme.

[1404] Such methods are described more fully in U.S. patent applicationSer. No. 60/019,790 filed Jun. 14, 1996 which application isincorporated herein by reference in its entirety. Briefly, PEPC isprepared by first reacting ethyl isocyanate with1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with4-toluenesulfonyl chloride to provide PEPC. The polymer supported formis prepared by reaction of PEPC with an appropriate resin under standardconditions to give the desired reagent.

[1405] The carboxylic acid coupling reactions employing these reagentsare performed at about ambient to about 45° C., for from about 3 to 120hours. Typically, the product may be isolated by washing the reactionwith CHCl₃ and concentrating the remaining organics under reducedpressure. As discussed supra, isolation of products from reactions wherea polymer bound reagent has been used is greatly simplified, requiringonly filtration of the reaction mixture and then concentration of thefiltrate under reduced pressure.

Preparation of Cyclic Amino Compounds

[1406] Cyclic amino compounds 2 employed in reaction (1) above aregenerally aminolactams, aminolactones, aminothiolactones andaminocycloalkyl compounds which can be represented by the formula:

[1407] where X is as defined above, Q is preferably selected from thegroup consisting of —O—, —S—, >NR⁶, and >CR⁷R⁸ where each of R⁶, R⁷ andR⁸ are independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl and heterocyclic with the provisothat if Q is —O—, —S— or >NR⁶, then X is oxo or dihydro, and W″ togetherwith Q, C═X and CH forms a lactone, thiolactone, lactam, cyclic ketone,cyclic alcohol, a heterocycle, and the like.

[1408] The aminolactams, aminolactones and aminothiolactones of theformula above can be prepared by use or adaptation of known chemicalsyntheses which syntheses are well described in the literature. See,e.g., Ogliaruso and Wolfe, Synthesis of Lactones and Lactams, Patai, etal. Editor, J. Wiley & Sons, New York, N.Y., USA, pp. 1085 et seq.(1993)¹⁵.

[1409] Specifically, 3-amino substituted lactams 13 with 5, 6 or 7 ringatoms may be prepared by the direct cyclization of a suitable alpha,omega-diamino acid ester 12 as shown in reaction (5) below:

[1410] wherein L is a linking group (typically an alkylene group) offrom 24 atoms, Pr is a suitable protecting group such ast-butoxycarbonyl, carbobenzyloxy, or the like and R⁹ is an alkoxy oraryloxy group such as methoxy, ethoxy, p-nitrophenoxy, N-succinimidoxy,and the like. The reaction may be carried out in a solvent such aswater, methanol, ethanol, pyridine, and the like. Such reactions areexemplified by cyclization of a lysine ester to a caprolactam asdescribed by Ugi, et al., Tetrahedron, 52(35):11657-11664 (1996)¹⁶.Alternatively, such a cyclization can also be conducted in the presenceof dehydrating agents such as alumina or silica to form lactams asdescribed by Blade-Font, Tetrahedron Lett., 21:2443 (1980)¹⁷.

[1411] The preparation of aminolactams alkylated on the amino group ofthe cyclic lactam is described by Freidinger, et al., J. Org. Chem.,47:104-109 (1982)¹⁸ and illustrated in reaction (6) below:

[1412] wherein L and R⁶ are as defined above.

[1413] In reaction (6), reductive amination of 14 with aldehyde 15 andsubsequent ring closure by methods using, for example, EDC provides foraminolactam 16. The preparation of 6 membered lactams using this generalprocedure is described by Semple, et al., J. Med. Chem., 39:4531-4536(1996)¹⁹.

[1414] The internal cyclization of an amide anion with a halide orequivalent thereof can sometimes be used to particular advantage in thesynthesis of smaller ring lactams where the stereochemistry of theamino-lactam center is available from the standard amino-acid pool. Thisapproach is illustrated in reaction (7) below:

[1415] where R⁶ is as defined above.

[1416] The approach of reaction (7) is presented by Semple, et al.,supra.¹⁹, and Freidinger, et al., J. Org. Chem., 47:104-109 (1982)¹⁸where a dimethylsulfonium leaving group is generated from methyl iodidetreatment of an alkyl methyl sulfide 17 to provide for lactam 18. Asimilar approach using a Mitsunobu reaction on an omega alcohol is foundHolladay, et al., J. Org. Chem., 56:3900-3905 (1991)²⁰.

[1417] In another method, lactams 20 can be prepared from cyclic ketones19 using either the well known Beckmnann rearrangement (e.g., Donaruma,et al., Organic Reactions, 11:1-156 (1960))²¹ or the well known Schmidtreaction (Wolff, Organic Reactions, 3:307-336 (1946))²² as shown inreaction (8) below:

[1418] wherein L is as defined above.

[1419] Application of these two reactions leads to a wide variety oflactams especially lactams having two hydrogen atoms on the carbon alphato the lactam carbonyl which lactams form a preferred group of lactamsin the synthesis of the compounds of formula I above. In thesereactions, the L group can be highly variable including, for example,alkylene, substituted alkylene and hetero containing alkylene with theproviso that a heteroatom is not adjacent to the carbonyl group ofcompound 19. Additionally, the Beckmann rearrangement can be applied tobicyclic ketones as described in Krow, et al., J. Org. Chem.,61:5574-5580 (1996)²³.

[1420] The preparation of lactones can be similarly conducted usingperacids in a Baeyer-Villiger reaction on ketones. Alternatively,thiolactones can be prepared by cyclization of an omega -SH group to acarboxylic acid and thiolactams can be prepared by conversion of the oxogroup to the thiooxo group by P₂S₅ or by use of the commerciallyavailable Lawesson's Reagent, Tetrahedron, 35:2433 (1979)²⁴.

[1421] One recently reported route for lactam synthesis is a variationof the Schmidt reaction through the use of an alkyl azide, eitherintermolecularly or intramolecularly, through a tethered alkylazidefunction that attacks a ketone under acidic conditions. Gracias, et al.,J. Am. Chem. Soc., 117:8047-8048 (1995)²⁵ describes the intermolecularversion whereas Milligan, et al., J. Am. Chem. Soc., 117:10449-10459(1995)²⁶ describes the intramolecular version. One example of theintramolecular version is illustrated in reaction (9) below:

[1422] where R¹⁰ is exemplified by alkyl, substituted alkyl, alkoxy,substituted alkoxy, aryl, heteroaryl, cycloalkyl and heterocyclic.

[1423] In this reaction, ketone 21 is converted to an α-(ω-alkyl)ketone22 which is cyclized to form bicyclic lactam 23. Such intramolecularreactions are useful in forming bicyclic lactams having 5-7 members andthe lactam ring of 6-13 members. The use of hetero atoms at non-reactivesites in these rings is feasible in preparing heterobicyclic lactams.

[1424] Still another recent approach to the synthesis of lactams isdescribed by Miller, et al., J. Am. Chem. Soc., 118:9606-9614 (1996)²⁷and references cited and is illustrated in reaction (10) below:

[1425] where R⁶ and Pr are as defined above and R¹¹ is exemplified byhalo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl,heteroaryl, cycloalkyl and heterocyclic wherein the aryl, heteroaryl,cycloalkyl and heterocyclic group is optionally fused to the lactam ringstructure.

[1426] Specifically, in reaction (10), lactam 26 is formed from anappropriate unsaturated amide (e.g., 24) through a ruthenium ormolybdenum complexes catalyzed olefin metathesis reaction to formunsaturated lactam 25 which can be used herein without furthermodification. However, the unsaturation in 25 permits a myriad oftechniques such a s hydroboration, Sharpless or Jacobsen epoxidations,Sharpless dihydroxylations, Diels-Alder additions, dipolar cycloadditionreactions and many more chemistries to provide for a wide range ofsubstituents on the lactam ring. Moreover, subsequent transformations ofthe formed substitution leads to other additional substituents (e.g.,mesylation of an alcohol followed by nucleophilic substitutionreactions). See, for example, March, et al. for a recitation of numeroussuch possible reactions.²⁸ Saturated amides used in this reaction areconventional with amide 24 being commercially available.

[1427] Related chemistry to cyclize amides to form lactams is disclosedby Colombo, et al., Tetrahedron Lett., 35(23):4031-4034 (1994)²⁹ and isillustrated in reaction (11) below:

[1428] In this reaction, proline derivative 27 is cyclized via atributyltin-radical cyclization to provide for lactam 28.

[1429] Some of the lactams described above contain the requisite aminogroup alpha to the lactam carbonyl whereas others did not. However, theintroduction of the required amino group can be achieved by any ofseveral routes delineated below which merely catalogue several recentliterature references for this synthesis.

[1430] For example, in a first general synthetic procedure, azide oramine displacement of a leaving group alpha to the carbonyl group of thelactam leads to the alpha-aminolactams. Such general syntheticprocedures are exemplified by the introduction of a halogen atomfollowed by displacement with phthalimide anion or azide and subsequentconversion to the amine typically by hydrogenation for the azide asdescribed in Rogriguez, et al., Tetrahedron, 52:7727-7736 (1996)³⁰,Parsons, et al., Biochem. Biophys. Res. Comm., 117:108-113 (1983)³¹ andWatthey, et al., J. Med. Chem., 28:1511-1516 (1985)³². One particularmethod involves iodination and azide displacement on, for example,benzyllactams as described by Armstrong, et al., Tetrahedron Lett.,35:3239 (1994)³³ and by King, et al., J. Org. Chem., 58:3384 (1993)³⁴.

[1431] Another example of this first general procedure for the synthesisof alpha-aminolactams from the corresponding lactam involvesdisplacement of a triflate group by an azido group as described by Hu,et al., Tetrahedron Lett., 36(21):3659-3662 (1995)³⁵.

[1432] Still another example of this first general procedure uses aMitsunobu reaction of an alcohol and a nitrogen equivalent (either —NH₂or a phthalimido group) in the presence of an azodicarboxylate and atriarylphosphine as described in Wada, et al., Bull. Chem. Soc. Japan,46:2833-2835 (1973)³⁶ using an open chain reagent.

[1433] Yet another example of this first general procedure involvesreaction of alpha-chlorolactams with anilines or alkyl amines in a neatmixture at 120° C. to provide for 2-(N-aryl or N-alkyl)lactams asdescribed by Gaetzi, Chem. Abs., 66:28690m.³⁷

[1434] In a second general synthetic procedure, reaction of an enolatewith an alkyl nitrite ester to prepare the alpha oxime followed byreduction yields the alpha-aminolactam compound. This general syntheticprocedure is exemplified by Wheeler, et al., Organic Syntheses, Coll.Vol. VI, p. 840³⁸ which describes the reaction of isoamyl nitrite with aketone to prepare the desired oxime. The reduction of the oxime methylester (prepared from the oxime by reaction with methyl iodide) isdescribed in the J. Med. Chem., 28(12):1886 (1985)³⁹ and the reductionof alpha-oximino caprolactams by Raney-nickel and palladium catalysts isdescribed by Brenner, et al., U.S. Pat. No. 2,938,029.⁴⁰

[1435] In a third general synthetic procedure, direct reaction of anenolate with an electrophilic nitrogen transfer agent can be used. Theoriginal reaction employed toluenesulfonyl azide but was improved asdescribed by Evans, et al., J. Am. Chem. Soc., 112:4011-4030 (1990)⁴¹.Specifically, direct introduction of an azido group which can be reducedto the amine by hydrogenation is described by Micouin, et al.,Tetrahedron, 52:7719-7726 (1996)⁴². Likewise, the use oftriisopropylbenzenesulfonyl azide as the azide transferring agent forreaction with an enolate is described by Evans, et al., supra. The useof triphenylphosphine to reduce the alpha-azidolactams to thecorresponding aminolactams in the benzodiazepine series is disclosed byButcher, et al., Tetrahedron Lett., 37(37):6685-6688 (1996).⁴³ Lastly,diazo transfer of beta-diketones and subsequent reduction of the diazogroup to the amino group is exemplified by Hu, et al., TetrahedronLett., 36(21):3659-3662 (1995)³⁵ who used Raney-nickel and hydrogen inacetic acid and acetic anhydride as the solvent.

[1436] In a fourth general procedure, N-substituted lactams are firstconverted to the 3-alkoxycarbonyl derivatives by reaction with a dialkylcarbonate and a base such as sodium hydride. See, for example, M. L.Reupple, et al., J. Am. Chem. Soc., 93:7021 et seq. (1971)⁴⁴ Theresulting esters serve as starting materials for conversion to the3-amino derivatives. This conversion is achieved via the Curtiusreaction as shown in reaction (12) below:

[1437] where Pr is as defined above and R¹² is typically hydrogen, analkyl or an aryl group.

[1438] The Curtius reaction is described by P. A. S. Smith, OrganicReactions, 3:337-449 (1946).⁴⁵ Depending on the reaction conditionschosen, Pr═H or a protecting group such as Boc. For example, when R═H,treatment of the acid with diphenylphosphoryl azide in the presence oft-butanol provides the product wherein Pr═Boc.

[1439] The alpha-aminolactams employed as the cyclic amino compounds 2in reaction (1) above include ring N-substituted lactams in addition toring N—H lactams. Some methods for preparing ring N-substituted lactamshave been described above. More generally, however, the preparation ofthese compounds range from the direct introduction of the substituentafter lactam formation to essentially introduction before lactamformation. The former methods typically employ a base and an primaryalkyl halide although it is contemplated that a secondary alkyl halidecan also be employed although yields may suffer.

[1440] Accordingly, a first general method for preparing N-substitutedlactams is achieved via reaction of the lactam with base and alkylhalide (or acrylates in some cases). This reaction is quite well knownand bases such as sodamide, sodium hydride, LDA, LiHMDS in appropriatesolvents such as THF, DMF, etc. are employed provided that the selectedbase is compatible with the solvent. See for example: K. Orito, et al.,Tetrahedron, 36:1017-1021 (1980)⁴⁶ and J. E. Semple, et al., J. Med.Chem., 39:4531-4536 (1996)¹⁹ (use of LiHMDS with either R-X or acrylatesas electrophiles).

[1441] A second general method employs reductive amination on an aminofunction which is then cyclized to an appropriate ester or othercarbonyl function.

[1442] A third general method achieves production of the N-substitutionduring lactam formation. Literature citations report such productionfrom either photolytic or thermal rearrangement of oxaziridines,particularly of N-aryl compounds. See, for example, Krimm, Chem. Ber.,91:1057 (1958)⁴⁷ and Suda, et al., J. Chem. Soc. Chem Comm., 949-950,(1994).⁴⁸ Also, the use of methyl hydroxylamine for the formation ofnitrones and their rearrangement to the N-methyl derivatives is reportedby Barton, et al., J. Chem. Soc., 1764-1767 (1975).⁴⁹ Additionally, theuse of the oxaziridine process in chiral synthesis has been reported byKitagawa, et al., J. Am. Chem. Soc., 117:5169-5178 (1975).⁵⁰

[1443] A more direct route to obtain N-phenyl substituted lactams fromthe corresponding NH lactams through the use oft-butyltetramethylguanidine and triphenylbismuth dichloride is disclosedby Akhatar, et al., J. Org. Chem., 55:5222-5225 (1990)⁵¹ as shown inreaction (13) below.

[1444] Given that numerous methods are available to introduce analpha-amino group onto a lactam (or lactone) ring, the following lactams(and appropriate corresponding lactones) are contemplated for use in thesynthesis of compounds of formula I above. Similar alcohol functions atthe carbonyl position are derivative of either amine ring opening ofcyclic epoxides, ring opening of aziridines, displacement of appropriatehalides with amine or alcohol nucleophiles, or most likely reduction ofappropriate ketones. These ketones are also of interest to the presentinvention.

[1445] Monocyclic lactams as described by Nedenskov, et al., Acta Chem.Scand., 12:1405-1410 (1958)⁵² are represented by the formula:

[1446] where R₁ and R₂ are exemplified by alkyl, aryl or alkenyl (e.g.,allyl).

[1447] Monocyclic lactams containing a second nitrogen ring atom asdescribed by Sakakida, et al., Bull. Chem. Soc. Japan, 44:478-480(1971)⁵³ are represented by the formula:

[1448] where R is exemplified by CH₃— or PhCH₂—.

[1449] Monocyclic lactams having hydroxyl substitution on the ring asdescribed by Hu, et al., Tetrahedron Lett., 36(21):3659-3662 (1995)³⁵are represented by the formula:

[1450] where R is exemplified by benzyl (includes both the cis and transhydroxy lactams).

[1451] The direct preparation N-substituted lactams of 5-8 members fromthe corresponding ketones is described by Hoffman, et al., Tet. Lett.,30:4207-4210 (1989).⁵⁴ These lactams are represented by the formula:

[1452] wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, or benzyl.

[1453] N-Methoxylactams prepared from cyclohexanone and dimethoxyamineare described by Vedejs, et al., Tet. Lett., 33:3261-3264 (1992).⁵⁵These structures are represented by the formula:

[1454] Substituted 3-aminoazetidinone derivatives prepared by a varietyof routes including those described by van der Steen, et al.,Tetrahedron, 47, 7503-7524 (1991)⁵⁶, Hart, et al., Chem Rev.,89:1447-1465 (1989)⁵⁷ and references cited therein are represented bythe formula:

[1455] where R₁ and R₂ are independently selected from alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl,heterocyclic or are fused to form a cyclic group.

[1456] Ring substituted lactams are described by Lowe, et al., Bioorg.Med. Chem. Lett., 4:2877-2882 (1994)⁵⁸ and are represented by theformula:

[1457] wherein R₂ and R₃ are exemplified by aryl and substituted aryland R₁ is exemplified by alkyl or hydrogen.

[1458] The synthesis of substituted 3-aminopyrrolidones fromalpha-bromoketones is described by McKennis, Jr., et al., J. Org. Chem.,28:383-387 (1963)⁵⁹. These compounds are represented by the formula:

[1459] where R¹ is aryl or heteroaryl and R² corresponds to anysubstituent for which the corresponding amine R²—NH₂ exists.

[1460] Additional references for the synthesis of alpha aminolactams areas follows:

[1461] 1. Shirota, et al., J. Med. Chem., 20:1623-1627 (1977)⁶⁰ whichdescribes the synthesis of

[1462] 2. Overberger, et al., J. Am. Chem. Soc., 85:3431 (1963)⁶¹ whichdescribes the preparation of optically active β-methylcaprolactam of theformula:

[1463] 3. Herschmann, Helv. Chim. Acta, 32:2537 (1949)⁶² describes thesynthesis of a disubstituted caprolactam from the Beckman rearrangementof menthone which is represented by the formula:

[1464] 4. Overberger, et al., Macromolecules, 1:1 (1968)⁶³ describes thesynthesis of eight-membered lactams from 3-methylcycloheptanone as shownbelow:

[1465] 5. The synthesis of benzolactams (benzazepinones) has beenreported by Busacca, et al., Tet. Lett., 33:165-168 (1992)⁶⁴:

[1466] by Croisier, et al., U.S. Pat. No. 4,080,449⁶⁵:

[1467] and by J. A. Robl, et al., Tetrahedron Lett., 36(10):1593-1596(1995)⁶⁶ who employed an internal Friedel-Crafts like cyclization toprepare the tricyclic benzyllactams shown below where Pht is thephthalimido protecting group:

[1468] Another tricyclic lactam series is disclosed by Flynn, et al., J.Med. Chem., 36:2420-2423 (1993)⁶⁷ and references cited therein.

[1469] 6. Orito, et al., Tetrahedron, 36:1017-1021 (1980)⁶⁸ disclosesphenyl substituted benzazepinones represented by the formula:

[1470] wherein R═H or CH₃—;

[1471] Kawase, et al., J. Org. Chem., 54:3394-3403 (1989)⁶⁹ discloses aN-methoxy benzazepinone represented by the formula:

[1472] 7. Lowe, et al., J. Med. Chem., 37:3789-3811 (1994)⁷⁰ describesseveral synthetic pathways to substituted benzazepinones of the formula:

[1473] where R₁ is substituted aryl or cyclohexyl, X is a suitablesubstituent and R₂ can be H or alkyl. The syntheses described in Loweare, however, adaptable to form numerous R¹ substituents.

[1474] 8. Robl, et al., Bioorg. Med. Chem. Lett., 4:1789-1794 (1994)⁷¹and references cited therein as well as Skiles, et al., Bioorg. Med.Chem. Lett., 3:773-778 (1993)⁷² disclose benzofused lactams whichcontain additional heteroatoms in the lactam ring. These compounds arerepresented by the formula:

[1475] where X is O and R₂═H or CH₃ or X═S and R₂═H. In either case,R₁═H or alkyl. Also, in Skiles, the thio group of the thiolactam can beoxidized to the SO₂ group. These structures are also presented fromBeckmann rearrangement in Grunewald, et al., J. Med. Chem., 39(18):3539(1996).⁷³

[1476] 9. Also syntheses for the benzoheterolactam series is presentedin Thomas, et al., J. Chem. Soc., Perkin II, 747 (1986)⁷⁴ which couldlead to compounds of the formula:

[1477] where X is O or H₂ and R is CO₂R.

[1478] 10. Further examples of benzazepinones are found in Warshawsky,et al., Bioorg. Med. Chem. Lett., 6:957-962 (1996)⁷⁵ which discloses

[1479] The synthesis can be generalized to produce R=alkyl or aryl.

[1480] 11. Ben-Ishai, et al., Tetrahedron, 43:439450 (1987)⁷⁶ describessyntheses which could lead to several benzolactams of the formula

[1481] wherein n=0,1,2 and R═—CH₃, PhCH₂— and H.

[1482] 12. van Niel et al., Bioorg. Med. Chem. Lett., 5:1421-1426(1995)⁷⁷ reports the synthesis of

[1483] wherein X is —OH, —NH₂ or —NR⁶R⁶ where R⁶ is as defined above.The reported ketone is a versatile synthetic intermediate which can bemodified by conventional methods such as reductive amination, reduction,etc.

[1484] 13. Kawase, et al., J. Org. Chem., 54:3394-3403 (1989)⁷⁸describes a synthetic method for the preparation of:

[1485] In addition to the above, saturated bicyclic alpha-aminolactamsare also contemplated for use in the synthesis of compounds of formulaI. Such saturated bicyclic alpha-aminolactams are well known in the art.For example, Edwards, et al., Can. J. Chem., 49:1648-1658 (1971)⁷⁹describes several syntheses of bicyclic lactams of the formula:

[1486] Similarly, Milligan, et al., J. Am. Chem. Soc., 117:10449-10459(1995)⁸⁰ and references cited therein report the synthesis of lactams ofthe formula:

[1487] wherein R1 and R2 are H or —CH₃, ring A can have from 6-13members and ring B can have from 5-7 members. R can be alkyl, aryl,cycloalkyl, and the like.

[1488] The introduction of a heteroatom into the saturated cyclicstructure fused to the lactam ring is disclosed by Curran et al., Tet.Lett., 36:191-194 (1995)⁸¹ who describe a synthetic method which can beused to obtain a lactam of the formula:

[1489] by Slusarchyk, et al., Bioorg. Med. Chem. Lett., 5:753-758(1995)⁸² who describe syntheses which could lead to a lactam of theformula:

[1490] and by Wyvratt, et al., Eur. Pat. Appl. 61187 (1982)⁸³ whodescribe a lactam of the formula:

[1491] Lactams having further heteroatom(s) in the cyclic lactamstructure (in addition to the nitrogen of the amido group of the lactam)are described by Cornille, et al., J. Am. Chem. Soc., 117:909-917(1995)⁸⁴ who describe lactams of the formula:

[1492] J. Kolc, Coll. Czech. Chem. Comm., 34:630 (1969)⁸⁵ who describeslysines suitable for cyclization to lactams which have a hetero lactamring atom as shown by the formula:

[1493] where X═O, S and NR where R is, for example, alkyl, substitutedalkyl, aryl, heteroaryl, heterocyclic, and the like.

[1494] Similarly, each of Dickerman, et al., J. Org. Chem., 14:530(1949)⁸⁶, Dickerman, et al., J. Org. Chem., 20:206 (1955)⁸⁷, andDickerman, et al., J. Org. Chem., 19:1855 (1954)⁸⁸ used the Schmidt andBeckmann reactions on substituted 4-piperidones to provide for lactamsof the formula:

[1495] where R is acyl, alkyl, substituted alkyl, aryl, heteroaryl orheterocyclic provided that R is not an acid labile group such as t-Boc;and R′ is hydrogen, alky, substituted alkyl, alkoxy, substituted alkoxy,aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclicoxy,halo, cyano, nitro, trihalomethyl, and the like.

[1496] An internal cyclization of appropriate ethylenediamine amidesonto a ketone or aldehyde is described by Hoffman, et al., J. Org.Chem., 27:3565 (1962)⁸⁹ as follows:

[1497] Ring expansion methodology based on beta lactams to provide forlarger ring lactams containing an aza group has twice been reported inWasserman, et al., J. Am. Chem. Soc., 103:461-2 (1981)⁹⁰ and in Crombie,et al., Tetrahedron Lett., 27(42):5151-5154 (1986).⁹¹

[1498] Dieckmann methodology has been used to prepare aza caprolactamsfrom unsymmetrical amines such as shown below by Yokoo, et al., Bull,Chem. Soc. Jap., 29:631 (1956).⁹²

[1499] where R is as defined in this reference. The disclosure of Yokoo,et al. can be extended to cover R being alkyl, substituted alkyl, aryl,alkoxy, substituted alkoxy, heteroaryl, cycloalkyl, heterocyclic,alkenyl, substituted alkenyl, and the like.

[1500] The synthesis of various members of the oxalactam series has beenreported by Burkholder, et al., Bioorg. Med. Chem. Lett., 2:231 (1993)⁹³and references cited therein which oxalactams are represented by theformula:

[1501] where 'R is as defined in the reference and R can be alkyl,substituted alkyl, aryl, alkoxy, substituted alkoxy, heteroaryl,cycloalkyl, heterocyclic, alkenyl, substituted alkenyl, and the like.

[1502] The synthesis of thialactams (generally oxalactams can be made bythe same methodology) has been reported by Freidinger, et al., J. Org.Chem., 47:104-109 (1982)¹⁸ who prepared thialactams of the formula:

[1503] This reference provides a series of procedures having broadapplication for synthesis of lactams permitting R in the above formulato be derived from any amine (alkyl, aryl, heteroaryl, etc.) with therestriction being that the R-group does not contain any functionalgroups reactive with formaldehyde (e.g., primary and secondary amines).The general synthetic scheme provided by Freidlinger, et al. is:

[1504] The coupling agent is any standard reagent used in the formationof typical peptide or amide bonds, for example, carbodiimide reagents.See, also, Karanewsky, U.S. Pat. No. 4,460,5799 and Kametani, et al.,Heterocycles, 9:831-840 (1978).⁹⁵

[1505] The Friedinger procedure can be extended to afford disubstitutedthialactams of the following structure:

[1506] In practical terms, R₂ will be limited to aryl and heteroarylgroups and sterically hindered alkyl groups such as t-butyl. R₁ can behighly variable and is limited only by subsequent reaction steps.

[1507] Still further is the Kametani procedure which provides forlactams as follows:

[1508] In principle, the Kametani procedure allows for a wide selectionof R1 and R2 groups limited primarily by stability to the reactionconditions.

[1509] See, for example, Yanganasawa, et al., J. Med. Chem.,30:1984-1991 (1987)⁹⁶ and J. Das et al., Biorg. Med. Chem. Lett.,4:2193-2198 (1994)⁹⁷ which describes general methods for the synthesisof isomeric 7-membered thialactams of the following structure:

[1510] The first synthetic route is:

[1511] R₂ can be highly variable (e.g., alkyl, substituted alkyl, aryl,heteroaryl, heterocyclic and the like) since a number of well documentedroutes exist for the synthesis of nitroethylene derivatives fromaldehydes and nitromethane (Henry reaction) followed by dehydration. R₁is limited to groups that can undergo alkylation reactions.

[1512] The second compound series can be prepared as follows:

[1513] In this synthesis, R₂ can be highly variable. The startingcomponent required to introduce R₂ can be readily derived by thereduction of any known alpha-BOC-amino acid to the alcohol derivativefollowed by formation of the mesylate.

[1514] As noted above, the primary approaches to the preparation oflactams is the Beckmann/Schmidt ring expansion reaction using eitherinter- or intramolecular approaches serves to prepare lactams of variousring sizes. The intramolecular approach generates bicyclic materialswith the lactam nitrogen incorporated into the ring fusion. Additionalapproaches set forth above are at the base of the methodology areinternal cyclization of omega-amino acids/esters where the constructionof the substituent pattern takes place prior to cyclization, andinternal cyclization of an electrophilic center onto a nucleophilicfunctional group as in the Friedel Crafts type cyclization at the centerof the Ben-Ishal procedure for making benzazepinones. This latterprocedure is applicable to a wide variety of heteroaromatics as well asbenzenoid rings, and may also be applied to non-aromatic double ortriple bonds to generate a wide array of substituents or ring fusions.

[1515] Deoxygenation of the lactam by reagents such as diborane, LiAlH₄,and the like leads to azaheterocycles (═X is dihydro).

[1516] Similarly, for X═H, OH, such compounds can be prepared byepoxidation of cycloalkenyl groups followed by oxirane opening by, e.g.,ammonia. After formation of compounds of formula I, ═X being H, OH canbe oxidized to provide for cycloalkylones (═X being oxo).

[1517] Additionally, the 5,7-dihydro-6H-diben[b,d]azepin-6-onederivatives employed in this invention can be prepared usingconventional procedures and reagents. For example, an appropriatelysubstituted N-tert-Boc-2-amino-2′-methylbiphenyl compound can becyclized to form the corresponding 5,7-dihydro-6H-diben[b,d]azepin-6-onederivative by first treating the biphenyl compound with about 2.1 toabout 2.5 equivalents of a strong base, such as sec-butyl lithium. Thisreaction is typically conducted at a temperature ranging from about −80°C. to about −60° C. in an inert diluent such as THF. The resultingdianion is then treated with dry carbon dioxide at a temperature ofabout −78° C. to afford the 5,7-dihydro-6H-diben[b,d]azepin-6-one. Thisprocedure is described further in R. D. Clark et al., Tetrahedron,49(7), 1351-1356 (1993) and references cited therein.

[1518] After forming the 5,7-dihydro-6H-diben[b,d]azepin-6-one, theamide nitrogen can be readily alkylated by first treating thedibenazepinone with about 1.1 to about 1.5 equivalents of a strong base,such as sodium hydride, in an inert diluent, such as DMF. This reactionis typically conducted at a temperature ranging from about −10° C. toabout 80° C. for about 0.5 to about 6 hours. The resulting anion is thencontacted with an excess, preferably about 1.1 to about 3.0 equivalents,of an alkyl halide, typically an alkyl chloride, bromide or iodide.Generally, this reaction is conducted at a temperature of about 0° C. toabout 100° C. for about 1 to about 48 hours.

[1519] An amino group can then be introduced at the 5-position of the7-alkyl-5,7-dihydro-6H-diben[b,d]azepin-6-one using conventionalprocedures and reagents. For example, treatment of7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one with an excess of butylnitrite in the presence of a strong base, such as potassium1,1,1,3,3,3-hexamethyldisilazane (KHMDS), affords5-oximo-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Subsequentreduction of the oximo group by hydrogenation in the presence of acatalyst, such as palladium on carbon, then provides5-amino-7-methyl-5,7-dihydro-6H-diben[b,d]azepin-6-one. Otherconventional amination procedures, such as azide transfer followed byreduction of the azido group, may also be employed.

[1520] Similarly, various benzodiazepine derivatives suitable for use inthis invention can be prepared using conventional procedures andreagents. For example, a 2-aminobenzophenone can be readily coupled toα-(isopropylthio)-N-(benzyloxycarbonyl)glycine by first forming the acidchloride of the glycine derivative with oxayl chloride, and thencoupling the acid chloride with the 2-aminobenzophenone in the presenceof a base, such as 4-methylmorpholine, to afford the2-[α-(isopropylthio)-N-(benzyloxycarbonyl)glycinyl]-aminobenzophenone.Treatment of this compound with ammonia gas in the presence of anexcess, preferably about 1.1 to about 1.5 equivalents, of mercury (II)chloride then affords the2-[N-(α-amino)-N′-(benzyloxycarbonyl)-glycinyl]aminobenzophenone. Thisintermediate can then be readily cyclized by treatment with glacialacetic acid and ammonium acetate to provide the3-(benzyloxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one1.Subsequent removal of the Cbz group affords the3-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one.

[1521] Alternatively, 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-onescan be readily aminated at the 3-position using conventional azidetransfer reactions followed by reduction of the resulting azido group toform the corresponding amino group. The conditions for these and relatedreactions are described in the examples set forth below. Additionally,2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-ones are readily alkylatedat the 1-position using conventional procedures and reagents. Forexample, this reaction is typically conducted by first treating thebenzodiazepinone with about 1.1 to about 1.5 equivalents of a base, suchas sodium hydride, potassium tert-butoxide, potassium1,1,1,3,3,3-hexamethyldisilazane, cesium carbonate, in an inert diluent,such as DMF. This reaction is typically conducted at a temperatureranging from about −78° C. to about 80° C. for about 0.5 to about 6hours. The resulting anion is then contacted with an excess, preferablyabout 1.1 to about 3.0 equivalents, of an alkyl halide, typically analkyl chloride, bromide or iodide. Generally, this reaction is conductedat a temperature of about 0° C. to about 100° C. for about 1 to about 48hours.

[1522] Additionally, the3-amino-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines employed inthis invention are typically prepared by first coupling malonic acidwith a 1,2-phenylenediamine. Conditions for this reaction are well knownin the art and are described, for example, in PCT Application WO96-US8400 960603. Subsequent alkylation and amination using conventionalprocedures and reagents affords various3-amino-1,5-bis(alkyl)-2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines.Such procedures are described in further detail in the example set forthbelow.

[1523] Accordingly, a vast number of lactams, lactones and thiolactonesare available by art recognized procedures. Similarly, the art isreplete with examples of aminocycloalkyl compounds for use in thesynthesis of compounds of formula I above.

[1524] In the synthesis of compounds of formula I using the syntheticmethods described above, the starting materials can contain a chiralcenter (e.g., alanine) and, when a racemic starting material isemployed, the resulting product is a mixture of R,S enantiomers.Alternatively, a chiral isomer of the starting material can be employedand, if the reaction protocol employed does not racemize this startingmaterial, a chiral product is obtained. Such reaction protocols caninvolve inversion of the chiral center during synthesis.

[1525] Accordingly, unless otherwise indicated, the products of thisinvention are a mixture of R,S enantiomers. Preferably, however, when achiral product is desired, the chiral product corresponds to the L-aminoacid derivative. Alternatively, chiral products can be obtained viapurification techniques which separates enantiomers from a R,S mixtureto provide for one or the other stereoisomer. Such techniques are wellknown in the art.

Pharmaceutical Formulations

[1526] When employed as pharmaceuticals, the compounds of formula I areusually administered in the form of pharmaceutical compositions. Thesecompounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal. These compounds are effective as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

[1527] This invention also includes pharmaceutical compositions whichcontain, as the active ingredient, one or more of the compounds offormula I above associated with pharmaceutically acceptable carriers. Inmaking the compositions of this invention, the active ingredient isusually mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier which can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

[1528] In preparing a formulation, it may be necessary to mill theactive compound to provide the appropriate particle size prior tocombining with the other ingredients. If the active compound issubstantially insoluble, it ordinarily is milled to a particle size ofless than 200 mesh. If the active compound is substantially watersoluble, the particle size is normally adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g. about 40mesh.

[1529] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include: lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl- and propylhydroxy-benzoates; sweetening agents; and flavoringagents. The compositions of the invention can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures known in theart.

[1530] The compositions are preferably formulated in a unit dosage form,each dosage containing from about 5 to about 100 mg, more usually about10 to about 30 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient. Preferably, the compound of formula I above isemployed at no more than about 20 weight percent of the pharmaceuticalcomposition, more preferably no more than about 15 weight percent, withthe balance being pharmaceutically inert carrier(s).

[1531] The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

[1532] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

[1533] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former. The two components can separated by entericlayer which serves to resist disintegration in the stomach and permitthe inner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

[1534] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

[1535] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

[1536] The following formulation examples illustrate the pharmaceuticalcompositions of the present invention.

Formulation Example 1

[1537] Hard gelatin capsules containing the following ingredients areprepared: Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch305.0 Magnesium stearate 5.0

[1538] The above ingredients are mixed and filled into hard gelatincapsules in 340 mg quantities.

Formulation Example 2

[1539] A tablet formula is prepared using the ingredients below:Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

[1540] The components are blended and compressed to form tablets, eachweighing 240 mg.

Formulation Example 3

[1541] A dry powder inhaler formulation is prepared containing thefollowing components: Ingredient Weight % Active Ingredient  5 Lactose95

[1542] The active ingredient is mixed with the lactose and the mixtureis added to a dry powder inhaling appliance.

Formulation Example 4

[1543] Tablets, each containing 30 mg of active ingredient, are preparedas follows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mgStarch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone4.0 mg (as 10% solution in sterile water) Sodium carboxymethyl starch4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg

[1544] The active ingredient, starch and cellulose are passed through aNo. 20 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinyl-pyrrolidone is mixed with the resultant powders, which arethen passed through a 16 mesh U.S. sieve. The granules so produced aredried at 50° to 60° C. and passed through a 16 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 30 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yield tabletseach weighing 150 mg.

Formulation Example 5

[1545] Capsules, each containing 40 mg of medicament are made asfollows: Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mgStarch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg

[1546] The active ingredient, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

Formulation Example 6

[1547] Suppositories, each containing 25 mg of active ingredient aremade as follows: Ingredient Amount Active Ingredient 25 mg Saturatedfatty acid glycerides to 2,000 mg

[1548] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7

[1549] Suspensions, each containing 50 mg of medicament per 5.0 ml doseare made as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthangum 4.0 mg Sodium carboxymethyl cellulose (11%) 50.0 mg Microcrystallinecellulose (89%) Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Colorq.v. Purified water to 5.0 ml

[1550] The active ingredient, sucrose and xanthan gum are blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of the microcrystalline cellulose and sodiumcarboxymethyl cellulose in water. The sodium benzoate, flavor, and colorare diluted with some of the water and added with stirring. Sufficientwater is then added to produce the required volume.

Formulation Example 8

[1551] Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg

[1552] The active ingredient, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 560 mg quantities.

Formulation Example 9

[1553] A subcutaneous formulation may be prepared as follows: IngredientQuantity Active Ingredient 1.0 mg corn oil 1 ml

[1554] (Depending on the solubility of the active ingredient in cornoil, up to about 5.0 mg or more of the active ingredient may be employedin this formulation, if desired).

Formulation Example 10

[1555] A topical formulation may be prepared as follows: IngredientQuantity Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin20 g White Soft Paraffin to 100 g

[1556] The white soft paraffin is heated until molten. The liquidparaffin and emulsifying wax are incorporated and stirred untildissolved. The active ingredient is added and stirring is continueduntil dispersed. The mixture is then cooled until solid.

[1557] Another preferred formulation employed in the methods of thepresent invention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See. e.g.,U.S. Pat. No. 5,023,252,issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

[1558] Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 which is herein incorporated byreference.

[1559] Indirect techniques, which are generally preferred, usuallyinvolve formulating the compositions to provide for drug latentiation bythe conversion of hydrophilic drugs into lipid-soluble drugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionswhich can transiently open the blood-brain barrier.

[1560] Other suitable formulations for use in the present invention canbe found in Remington's Pharmaceutical Sciences, Mace PublishingCompany, Philadelphia, Pa., 17th ed. (1985).

Utility

[1561] The compounds and pharmaceutical compositions of the inventionare useful in inhibiting β-amyloid peptide release and/or its synthesis,and, accordingly, have utility in diagnosing and treating Alzheimer'sdisease in mammals including humans.

[1562] As noted above, the compounds described herein are suitable foruse in a variety of drug delivery systems described above. Additionally,in order to enhance the in vivo serum half-life of the administeredcompound, the compounds may be encapsulated, introduced into the lumenof liposomes, prepared as a colloid, or other conventional techniquesmay be employed which provide an extended serum half-life of thecompounds. A variety of methods are available for preparing liposomes,as described in, e.g., Szoka, et al., U.S. Pat. Nos. 4,235,871,4,501,728 and 4,837,028 each of which is incorporated herein byreference.

[1563] The amount of compound administered to the patient will varydepending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions are administered to a patient alreadysuffering from AD in an amount sufficient to at least partially arrestfurther onset of the symptoms of the disease and its complications. Anamount adequate to accomplish this is defined as “therapeuticallyeffective dose.” Amounts effective for this use will depend on thejudgment of the attending clinician depending upon factors such as thedegree or severity of AD in the patient, the age, weight and generalcondition of the patient, and the like. Preferably, for use astherapeutics, the compounds described herein are administered at dosagesranging from about 1 to about 500 mg/kg/day.

[1564] In prophylactic applications, compositions are administered to apatient at risk of developing AD (determined for example by geneticscreening or familial trait) in an amount sufficient to inhibit theonset of symptoms of the disease. An amount adequate to accomplish thisis defined as “prophylactically effective dose.” Amounts effective forthis use will depend on the judgment of the attending cliniciandepending upon factors such as the age, weight and general condition ofthe patient, and the like. Preferably, for use as prophylactics, thecompounds described herein are administered at dosages ranging fromabout 1 to about 500 mg/kg/day.

[1565] As noted above, the compounds administered to a patient are inthe form of pharmaceutical compositions described above. Thesecompositions may be sterilized by conventional sterilization techniques,or may be sterile filtered. The resulting aqueous solutions may bepackaged for use as is, or lyophilized, the lyophilized preparationbeing combined with a sterile aqueous carrier prior to administration.The pH of the compound preparations typically will be between 3 and 11,more preferably from 5 to 9 and most preferably from 7 and 8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of pharmaceutical salts.

[1566] The compounds described herein are also suitable for use in theadministration of the compounds to a cell for diagnostic and drugdiscovery purposes. Specifically, the compounds may be used in thediagnosis of cells releasing and/or synthesizing β-amyloid peptide. Inaddition the compounds described herein are useful for the measurementand evaluation of the activity of other candidate drugs on theinhibition of the cellular release and/or synthesis of β-amyloidpeptide.

[1567] The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention.

EXAMPLES

[1568] In the examples below, the following abbreviations have thefollowing meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning. BEMP = 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine Boc = t-butoxycarbonyl BOP =benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphatebd = broad doublet bs = broad singlet d = doublet dd = doublet ofdoublets DIC = diisopropylcarbodiimide DMF = dimethylformamide DMAP =dimethylaminopyridine DMSO = dimethylsulfoxide EDC =ethyl-1-(3-dimethyaminopropyl)carbodiimide eq. = equivalents EtOAc =ethyl acetate g = grams HOBT = 1-hydroxybenzotriazole hydrate Hunig'sbase = diisopropylethylamine L = liter m = multiplet M = molar max =maximum meq = milliequivalent mg = milligram mL = milliliter mm =millimeter mmol = millimole MOC = methoxyoxycarbonyl N = normal N/A =not available ng = nanogram nm = nanometers OD = optical density PEPC =1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide PP-HOBT =piperidine-piperidine-1-hydroxybenzotrizole psi = pounds per square inchφ = phenyl q = quartet quint. = quintet rpm = rotations per minute s =singlet t = triplet TFA = trifluoroacetic acid THF = tetrahydrofuran tlc= thin layer chromatography μL = microliter UV = ultra-violet

[1569] In the examples below, all temperatures are in degrees Celcius(unless otherwise indicated). The compounds set forth in the examplesbelow were prepared using the following general procedures as indicated.

[1570] In the following examples and procedures, the term “Aldrich”indicates that the compound or reagent used in the procedure iscommercially available from Aldrich Chemical Company, Inc., 1001 WestSaint Paul Avenue, Milwaukee, Wis. 53233 USA; the term “Fluka” indicatesthat the compound or reagent is commercially available from FlukaChemical Corp., 980 South 2nd Street, Ronkonkoma N.Y. 11779 USA; theterm “Lancaster” indicates that the compound or reagent is commerciallyavailable from Lancaster Synthesis, Inc., P.O. Box 100 Windham, N.H.03087 USA; the term “Sigma” indicates that the compound or reagent iscommercially available from Sigma, P.O. Box 14508, St. Louis Mo. 63178USA; the term “Chemservice” indicates that the compound or reagent iscommercially available from Chemservice Inc., Westchester, Pa.; the term“Bachem” indicates that the compound or reagent is commerciallyavailable from Bachem Biosciences Inc., 3700Horizon Drive, Renaissanceat Gulph Mills, King of Prussia, Pa. 19406 USA; the term “Maybridge”indicates that the compound or reagent is commercially available fromMaybridge Chemical Co. Trevillett, Tintagel, Cornwall PL34 OHW UnitedKingdom; and the term “TCI” indicates that the compound or reagent iscommercially available from TCI America, 9211 North Harborgate Street,Portland Oreg. 97203; the term “Alfa” indicates that the compound orreagent is commercially available from Johnson Matthey Catalog Company,Inc. 30 Bond Street, Ward Hill, Mass. 01835-0747; the term “Novabiochem”indicates that the compound or reagent is commercially available fromCalbiochem-Novabiochem Corp. 10933 North Torrey Pines Road, P.O. Box12087, La Jolla Calif. 92039-2087; the term “Oakwood” indicates that thecompound or reagent is commercially available from Oakwood, Columbia,S.C.; the term “Advanced Chemtech” indicates that the compound orreagent is commercially available from Advanced Chemtech, Louisville,Ky.; and the term “Pfaltz & Bauer” indicates that the compound orreagent is commercially available from Pfaltz & Bauer, Waterbury, Conn.,USA.

[1571] I. Coupling Procedures

General Procedure A First EDC Coupling Procedure

[1572] To a 1:1 mixture of the corresponding carboxylic acid and thecorresponding amino acid ester or amide in CH₂Cl₂ at 0° C. was added 1.5equivalents triethylamine, followed by 2.0 equivalentshydroxybenzotriazole monohydrate and then 1.25 equivalents ofethyl-3-(3-dimethylamino)propyl carbodiimide HCl. The reaction mixturewas stirred overnight at room temperature and then transferred to aseparatory funnel. The mixture was washed with water, saturated aqueousNaHCO₃, 1N HCl and saturated aqueous NaCl, and then dried over MgSO₄.The resulting solution was stripped free of solvent on a rotaryevaporator to yield the crude product.

General Procedure B Second EDC Coupling Procedure

[1573] A mixture of the corresponding acid (1 eqv),N-1-hydroxybenzotriazole (1.6 eqv), the corresponding amine (1 eqv),N-methylmorpholine (3 eqv) and dichloromethane (or DMF for insolublesubstrates) was cooled in an ice-water bath and stirred until a clearsolution was obtained. EDC (1.3 eqv) was then added to the reactionmixture. The cooling bath was then allowed to warm to ambienttemperature over 1-2 h and the reaction mixture was stirred overnight.The reaction mixture was then evaporated to dryness under vacuum. To theresidue was added 20% aqueous potassium carbonate and the mixture wasshaken throughly and then allowed to stand until the oily productsolidified (overnight if necessary). The solid product was thencollected by filteration, washed thoroughly with 20% aqueous potassiumcarbonate, water, 10% HCl, and water to give the product, usually inpure state. No racemization was observed.

General Procedure C Third EDC Coupling Procedure

[1574] The carboxylic acid was dissolved in methylene chloride. Thecorresponding amino acid ester or amide (1 eq.), N-methylmorpholine (5eq.) and hydroxybenzotriazole monohydrate (1.2 eq.) were added insequence. A cooling bath was applied to the round bottomed flask untilthe solution reached 0° C. At that time, 1.2 eq. of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added.The solution was allowed to stir overnight and come to room temperatureunder nitrogen pressure. The reaction mixture was worked up by washingthe organic phase with saturated aqueous sodium carbonate, 0.1M citricacid, and brine before drying with sodium sulfate. The solvents werethen removed to yield crude product.

General Procedure D Fourth EDC Coupling Procedure

[1575] A round bottom flask was charged with the correspondingcarboxylic acid (1.0 eq.), hydroxybenzotriazole hydrate (1.1 eq.) andthe corresponding amine (1.0 eq.) in THF under nitrogen atmosphere. Anappropriate amount (1.1 eq for free amines and 2.2 eq. for hydrochlorideamine salts) of base, such as Hunig's base was added to the well stirredmixture followed by EDC (1.1 eq.). After stirring from 4 to 17 hours atroom temperature the solvent was removed at reduced pressure, theresidue taken up in ethyl acetate (or similar solvent) and water, washedwith saturated aqueous sodium bicarbonate solution, 1 N HCl, brine,dried over anhydrous sodium sulfate and the solvent removed at reducedpressure to provide the product.

General Procedure E BOP Coupling Procedure

[1576] To a stirred solution of N-(3,5-difluorophenylacetyl)alanine (2mmol) in DMF, cooled in an ice-water bath, was added BOP (2.4 mmol) andN-methylmorpholine (6 mmol). The reaction mixture was stirred for 50min. and then a solution of α-amino-γ-lactam (2 mmol) in DMF cooled at 0° C. was added. The cooling bath was allowed to warm to ambienttemperature over 1-2 h and the reaction mixture was then stirredovernight. A 20% aqueous potassium carbonate solution (60 mL) was addedand this mixture shaken throughly. No solid formed. The mixture was thenwashed with ethyl acetate (150 mL) and evaporated to dryness undervacuum to give a white solid. Water (50 mL) was then added and thismixture shaken throughly. The precipitate that formed was collected byfiltration, then washed thoroughly with water, followed by 1 mL ofdiethyl ether to give the product (51 mg, 0.16 mmol, 7.8%).

General Procedure F Coupling of an Acid Chloride with an Amino AcidEster

[1577] To a stirred solution of (D,L)-alanine isobutyl esterhydrochloride (4.6 mmol) in 5 ml of pyridine was added 4.6 mmol of theacid chloride. Precipitation occurred immediately. The mixture wasstirred for 3.5 h, dissolved in 100 mL of diethyl ether, washed with 10%HCl three times, brine once, 20% potassium carbonate once and brineonce. The solution was dried over magnesium sulfate, filtered, andevaporated to yield the product. Other amino acid esters may also beemployed in this procedure.

General Procedure G Coupling of a Carboxylic Acid with an Amino AcidEster

[1578] A solution of the carboxylic acid (3.3 mmol) and1,1′-carbodiimidazole (CDI) in 20 mL THF was stirred for 2 h.(D,L)-alanine isobutyl ester hydrochloride (3.6 mmol) was added,followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction mixturewas stirred overnight. The reaction mixture was dissolved in 100 mL ofdiethyl ether, washed with 10% HCl three times, brine once, 20%potassium carbonate once and brine once. The solution was dried overmagnesium sulfate, filtered, and evaporated to yield the product. Otheramino acid esters may also be employed in this procedure.

General Procedure H Fifth EDC Coupling Procedure

[1579] In a round bottom flask was added a carboxylic acid (1.1 eq.) inTHF, an amine hydrochloride (1.0 eq.), 1-hydroxybenzotriazole hydrate(1.1 eq.), N,N-diisopropylethylamine (2.1 eq.), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.1eq.). The reaction mixture stirred at room temperature for 10-20 hoursunder an atmosphere of nitrogen. The mixture was diluted with EtOAc andwashed with 0.1 M HCl (1×10 mL), saturated NaHCO₃ (1×10 mL), H₂O (1×10mL), and brine and dried over MgSO₄. The drying agent was removed byfiltration and the filtrate was concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel followed bytrituration from EtOAc and hexanes.

General Procedure I Sixth EDC Coupling Procedure

[1580] To a solution or suspension of the amine or amine hydrochloride(1.0 eq.) in THF (0.05-0.1 M) under N₂ at 0° C. was added the carboxylicacid (1.0-1.1 eq.), hydroxybenzotriazole monohydrate (1.1-1.15 eq.),Hunig's base (1.1 eq. for free amines and 1.1-2.3 eq. for hydrochlorideamine salts), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (1.1-1.15 eq.). The cooling bath was removed and themixture allowed to warm to room temperature for 10-24 hours. Thesolution or mixture was diluted with EtOAc, in a 3-5 volume multiple ofthe initial THF volume, and washed with 0.1-1.0 M aq. HCl (1 or 2×),dilute NaHCO₃ (1 or 2×), and brine (1×). Then, the organic phase wasdried over either MgSO₄ or Na₂SO₄, filtered, concentrated to provide thecrude product, which was either further purified or utilized withoutfurther purification.

General Procedure J EEDQ Coupling Procedure

[1581] To a solution of the amine in THF (1.0 eq., 0.05-0.08 M, finalmolarity) under N₂ at room temperature was added the N-t-Boc protectedamino acid (1.1 eq., either as a solid or in THF via cannula), followedby EEDQ (Aldrich, 1.1 eq.). The pale yellow solution was stirred at roomtemperature for 16-16.5 hours, then diluted with EtOAc (in a 3-5 volumemultiple of the initial THF volume), and washed with 1M aq. HCl (2×),dilute aq. NaHCO₃ (2×), and brine (1×). The organic phase was dried overeither Na₂SO₄ or MgSO₄, filtered, and concentrated.

[1582] II. Carboxylic Acids

General Procedure II-A Ester Hydrolysis to Free Acid

[1583] Ester hydrolysis to the free acid was conducted by conventionalmethods. Below are two examples of such conventional de-esterificationmethods.

[1584] Method A: To a carboxylic ester compound in a 1:1 mixture ofCH₃OH/H₂O was added 2-5 equivalents of K₂CO₃. The mixture was heated to50° C. for 0.5 to 1.5 hours until tlc showed complete reaction. Thereaction was cooled to room temperature and the methanol was removed ona rotary evaporator. The pH of the remaining aqueous solution wasadjusted to ˜2, and ethyl acetate was added to extract the product. Theorganic phase was then washed with saturated aqueous NaCl and dried overMgSO₄. The solution was stripped free of solvent on a rotary evaporatorto yield the product.

[1585] Method B: The amino acid ester was dissolved in dioxane/water(4:1) to which was added LiOH (˜2 eq.) that was dissolved in water suchthat the total solvent after addition was about 2:1 dioxane:water. Thereaction mixture was stirred until reaction completion and the dioxanewas removed under reduced pressure. The residue was dissolved in waterand washed with ether. The layers were separated and the aqueous layerwas acidified to pH 2. The aqueous layer was extracted with ethylacetate. The ethyl acetate extracts were dried over Na₂SO₄ and thesolvent was removed under reduced pressure after filtration. The residuewas purified by conventional methods (e.g., recrystallization).

General Procedure II-B Acid Chloride Preparation

[1586] 3,5:Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) wasdissolved in dichloromethane and this solution was cooled to 0C. DMF(0.5 mL, catalytic) was added followed by the dropwise addition ofoxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reactionwas stirred for 3 h and then rotoevaporated at reduced pressure to givean oil which was placed on a high vacuum pump for 1 h to afford3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acidchlorides can be prepared in a similar manner.

General Procedure II-C Schotten-Baumann Procedure

[1587] 3,5-Difluorophenylacetyl chloride (from General Procedure II-B)was added dropwise to a 0° C. solution of L-alanine (Aldrich) (16.7 g,0.187 mol) in 2 N sodium hydroxide (215 mL, 0.43 mol). The reaction wasstirred for 1 h at 0° C. and then overnight at room temperature. Thereaction was diluted with water (100 mL), then extracted with ethylacetate (3×150 mL). The organic layer was then washed with brine (200mL), dried over MgSO₄, and rotoevaporated at reduced pressure to aresidue. Recrystallization of the residue from ethyl acetate/hexanesafforded the desired product (34.5 g, 82% yield). Other acid chloridesmay be used in this procedure to provide for intermediates useful inthis invention.

General Procedure II-D Reductive Amination

[1588] To a solution of the arylamine in ethanol in a hydrogenationflask was added 1 equivalent of the 2-oxocarboxylic acid ester (e.g.,pyruvate ester), followed by 10% palladium on carbon (25 weight percentbased on the arylamine). The reaction was hydrogenated at 20 psi H₂ on aParr shaker until complete reaction was indicated by tlc (30 minutes to16 hours). The reaction mixture was then filtered through a pad ofCelite 545 (available from Aldrich Chemical Company, Inc.) and strippedfree of solvent on a rotary evaporator. The crude product residue wasthen further purified via chromatography.

Example A Synthesis of N-(Phenylacetyl)-L-alanine

[1589] Using General Procedure II-C, the title compound was preparedfrom phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solidhaving a melting point of 102-104° C.

[1590] NMR data was as follows:

[1591]¹H-nmr (CDCl₃): δ=9.14 (br s, 1H), 7.21-7.40 (m, 5H), 6.20 (d,J=7.0 Hz, 1H), 4.55 (m, 1H), 3.61 (s, 2H), 1.37 (d, J=7.1 Hz, 3H).

[1592]¹³C-nmr (CDCl₃): δ=176.0, 171.8, 134.0, 129.4, 127.5, 48.3, 43.2,17.9.

Example B Synthesis of N-(3,5-Difluorophenylacetyl)-L-alanine

[1593] Using General Procedure II-C, the title compound was preparedfrom 3,5-difluorophenylacetyl chloride (General Procedure II-B) andL-alanine (Aldrich).

[1594] NMR data was as follows:

[1595]¹H-nmr (CD₃OD): δ=8.32 (br s, 0.3H), 6.71 (m, 2H), 6.60 (m, 1H),4.74 (br s, 1.7H), 4.16 (m, 1H), 3.36 (s, 2H), 1.19 (d, J=7.3 Hz, 3H).

[1596]¹³C-nmr (CD₃OD): δ=175.9, 172.4, 164.4 (dd, J=13.0, 245.3 Hz),141.1, 113.1 (dd, J=7.8, 17.1 Hz), 102.9 (t, J=25.7 Hz), 49.5, 42.7,17.5.

Example C Synthesis of N-(Cyclopentylacetyl)-L-phenylglycine StepA—Preparation of N-(Cyclopentylacetyl)-L-phenylglycine Methyl Ester

[1597] Following General Procedure A above using cyclopentylacetic acid(Aldrich) and phenylglycine methyl ester hydrochloride (Novabiochem),the title compound was prepared as a solid having a melting point of83-86° C. The reaction was monitored by tlc on silica gel (Rf=0.28 in25% ethyl acetate/hexanes) and purification was by recrystallizationfrom ethyl acetate/hexanes.

[1598] NMR data was as follows:

[1599]¹H-nmr (CDCl₃): δ=7.35 (s, 5H), 6.44 (bd, 1H), 5.6 (d, 1H), 3.72(s, 3H 2.24 (bs, 3H), 1.9-1.4 (m, 6H), 1.2-1.05 (m, 2H).

[1600]¹³C-nmr (CDCl₃): δ=172.3, 171.7, 136.7, 129.0, 128.6, 127.3, 56.2,52.7, 42.5, 36.9, 32.40, 32.38, 24.8.

[1601] C₁₆H₂₁NO₃ (MW=275.35); mass spectroscopy (M+Na) 298.

Step B—Preparation of N-(Cyclopentylacetyl)-L-phenylglycine

[1602] Following General Procedure II-A above usingN-(cyclopentylacetyl)-L-phenylglycine methyl ester (from Step A), thetitle compound was prepared as a solid having a melting point of155-158° C. The reaction was monitored by tlc on silica gel (Rf=0.18 in10% methanol/dichloromethane).

[1603] NMR data was as follows:

[1604]¹H-nmr (CDCl₃): δ=8.60 (d, J=7.8 Hz, 1H), 7.45 (m, 5H0, 5.41 (d,J=7.2 Hz, 1H), 2.20 (m, 3H), 1.8-1.1 (m, 8H).

[1605]¹³C-nmr (CDCl₃): δ=172.3, 172.0, 137.5, 128.7, 128.1, 127.8, 56.2,40.9, 36.8, 31.8, 24.5.

[1606] C₁₅H₁₉NO₃ (MW=261.32); mass spectroscopy (M+Na) 284.

Example D Synthesis of N-(Cyclopentylacetyl)-L-alanine StepA—Preparation of N-(Cyclopentylacetyl)-L-alanine Methyl Ester

[1607] Following General Procedure A above using cyclopentylacetic acid(Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the titlecompound was prepared as a solid having a melting point of 43-46° C.Purification was by recrystallization from ethyl acetate/hexanes.

[1608] NMR data was as follows:

[1609]¹H-nmr (CDCl₃): δ=6.38 (d, 1H), 4.50 (m, 1H), 3.65 (s, 3H), 2.13(bs, 3H), 1.80-1.00 (m (includes d at 1.30, 3H), 11H).

[1610]¹³C-nmr (CDCl₃): δ=173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15,32.14, 18.0.

[1611] C₁₁H₁₉NO₃ (MW=213.28); mass spectroscopy (MH⁺) 214.

Step B—Preparation of N-(Cyclopentylacetyl)-L-alanine

[1612] Following General Procedure II-A above usingN-(cyclopentylacetyl)-L-alanine methyl ester (from Step A), the titlecompound was prepared. The reaction was monitored by tlc on silica gel(Rf=0.18 in 10% methanol/dichloromethane).

[1613] NMR data was as follows:

[1614]¹H-nmr (DMSO-d₆): δ=12.45 (bs, 1H), 8.12 (d, J=7.2 Hz, 1H), 4.24(quint, J=7.2 Hz, 1H), 2.14 (m, 3H), 1.8-1.4 (m, 6H), 1.29 (d, J=7.2 Hz,3H), 1.2-1.0 (m, 3H).

[1615]¹³C-nmr (DMSO-d₆): δ=174.6, 171.9, 47.3, 41.1, 36.7, 31.8, 24.5,17.2.

[1616] C₁₀H₁₇NO₃ (MW=199.25); mass spectroscopy (MH⁺) N/A.

Example E Synthesis of N-(Cyclopropylacetyl)-L-alanine StepA—Preparation of N-(Cyclopropylacetyl)-L-alanine Methyl Ester

[1617] Following General Procedure A above using cyclopropylacetic acid(Aldrich) and L-alanine methyl ester hydrochloride (Sigma), the titlecompound was prepared as an oil. The reaction was monitored by tlc onsilica gel (Rf=0.15 in 25% ethyl acetate/hexanes) and purification wasby flash column chromatography using 25% ethyl acetate/hexanes as theeluant.

[1618] NMR data was as follows:

[1619]¹H-nmr (CDCl₃): δ=6.60 (d, 1H), 4.55 (m, 1H), 3.69 (s, 3H), 2.10(m, 2H), 1.34 (d, 3H), 0.95 (m, 1H), 0.58 (m, 2H), 0.15 (m, 2H).

[1620]¹³C-nmr (CDCl₃): δ=173.7, 172.3, 52.3, 47.7, 41.0, 18.2, 6.7,4.27, 4.22.

[1621] C₉H₁₅NO₃ (MW=185.22); mass spectroscopy (MH⁺) N/A.

Step B—Preparation of N-(Cyclopentylacetyl)-L-alanine

[1622] Following General Procedure II-A above usingN-(cyclopropylacetyl)-L-alanine methyl ester (from Step A), the titlecompound was prepared as an oil. The reaction was monitored by tlc onsilica gel (Rf=0.27 in 10% methanol/dichloromethane).

[1623] NMR data was as follows:

[1624]¹H-nmr (DMSO-d₆): δ=8.18 (d, 1H), 4.25 (m, 1H), 2.08 (m, 2H), 1.30(d, 3H), 1.00 (m, 1H), 0.50 (m, 2H), 0.19 (m, 2H).

[1625]¹³C-nmr (DMSO-d₆): δ=174.6, 171.7, 47.4, 17.3, 7.6, 4.12, 4.06.

[1626] C₈H₁₃NO₃ (MW=199.25); mass spectroscopy (MH⁺) N/A.

Example F Synthesis of N-(Cyclopropylacetyl)-L-phenylglycine StepA—Preparation of N-(Cyclopropylacetyl)-L-glycine Methyl Ester

[1627] Following General Procedure A above using cyclopropylacetic acid(Aldrich) and L-phenylglycine methyl ester, the title compound wasprepared as a solid having a melting point of 74-76° C. The reaction wasmonitored by tlc on silica gel (Rf=0.61 in 50% ethyl acetate/hexanes)and purification was by recrystallization from ethyl acetate/hexanes.

[1628] NMR data was as follows:

[1629]¹H-nmr (CDCl₃): δ=7.35 (m, 5H), 6.97 (bd, J=7.2 Hz, 1H), 5.59 (d,J=7.8 Hz, 1H), 3.71 (s, 3H), 2.17 (m, 2H), 1.05-0.95 (m, 1H), 0.62 (m,2H), 0.20 (m, 2H).

[1630]¹³C-nmr (CDCl₃): δ=171.9, 174.6, 136.6, 129.0, 128.5, 127.2, 56.1,52.7, 41.0, 6.9, 4.37, 4.33.

[1631] C₁₄H₁₇NO₃ (MW=247.30); mass spectroscopy (MH⁺) N/A.

Step B—Preparation of N-(Cyclopentylacetyl)-L-phenylglycine

[1632] Following General Procedure II-A above usingN-(cyclopropylacetyl)-L-phenylglycine methyl ester (from Step A), thetitle compound was prepared as a solid having melting point of 152-157°C. The reaction was monitored by tlc on silica gel (Rf=0.23 in 10%methanol/dichloromethane) and purification was by recrystallization fromethyl acetate/hexanes.

[1633] NMR data was as follows:

[1634]¹H-nmr (CDCl₃): δ=8.47 (d, J=7.69 Hz, 1H), 7.35 (m, 5H), 5.34 (d,J=7.69 Hz, 1H), 2.10 (m, 2H), 0.90 (m, 1H), 0.40 (m, 2H), 0.10 (m, 2H).

[1635]¹³C-nmr (CDCl₃): δ=172.3, 171.8, 137.6, 128.7, 56.2, 7.7, 4.0.

[1636] C₁₃H₁₅NO₃ (MW=233.27); mass spectroscopy (MH⁺) N/A.

Example H Synthesis of N-(2-Biphenyl)-D,L-alanine

[1637] 2-Aminobiphenyl (2 g, 11.8 mmol, Aldrich), triethylamine (1.2eq.) and ethyl 2-bromopropionate (1.1 eq., Aldrich) were combined andheated to 85° C. with stirring. After 7 days, the mixture was dilutedwith chloroform and washed with water. The organic portion was dried andconcentrated to yield an oil which was purified by silica gelchromatography (1:1 CH₂Cl₂/hexanes). The resulting oil was dissolved ina 1:2 mixture of water/dioxane (200 mL) and LiOH (2 eq.) was added.After 2 hours, the mixture was concentrated to yield an oil which wasdissolved in water. The aqueous solution was washed with ether then wasadjusted to pH 3 with 5N HCl and extracted with ethyl acetate. Theorganic portion was dried and concentrated to yield an oil which waspurified by silica gel chromatography (EtOAc) to yield the titlecompound.

Example I Synthesis of N-(Phenyl-furazan-3-yl)-D,L-alanine

[1638] Following General Procedure II-D and using4-phenyl-furazan-3-ylamine (Maybridge) and ethyl pyruvate (Aldrich), theethyl ester was prepared. Following General Procedure II-A, Method B(LiOH/H₂O/dioxane) and using the ethyl ester, the title compound wasprepared.

Example L Synthesis of S-(+)-3,5-Difluoromandelic Acid StepA—Preparation of Methyl S-(±)-3.5-difluoromandelate

[1639] To a solution of 3,5-difluorobenzaldehyde (Aldrich) in CH₂Cl₂(100 mL) was added ZnCl₂ (6.7 g, 21.1 mmol) to form a slurry.Trimethysilyl cyanide (21.0 g, 211.2 mmol) dissolved in CH₂Cl₂ (100 mL)was slowly added to the slurry at 0° C. The resulting solution wasstirred at room temperature for 4 h. The reaction mixture was thendiluted with water and the organic layer separated. The combined organiclayers were concentrated to a residue. The residue was dissolved withMeOH (200 mL) at 0° C. and anhydrous HCl gas bubbled into the solutionfor 10 min. After stirring at room temperature for 18 h, the solutionwas concentrated to a solid. The solid was dissolved in CH₂Cl₂/H₂O andthe aqueous portion extracted with CH₂Cl₂. The combined organics werewashed with brine, dried over anhydrous MgSO₄ and concentrated to asolid (37.4 g, 87.6%), mp=77-78° C.

[1640]¹H NMR (300 MHz, CDCl₃): δ=6.97 (dd, J=9.6 Hz, J=1.79 Hz, 2H),6.74 (dt, J=8.82, J=2.28 Hz, 1H), 5.14 (d, J=4.64 Hz, 1H), 3.78 (s, 3H),3.54 (d, J=5.1 Hz, 1H).

Step B—Preparation of Methyl S-(+)-3,5-difluoromandelate

[1641] Methyl (±)-3,5-difluoromandelate was separated via preparativechiral HPLC to give a white solid having a melting point of 70-71° C.

[1642] C₉H₈F₂O₃ (MW=202.17); mass spectroscopy found (M+NH₄ ⁺) 220.0.

[1643] Anal. calcd for C₉H₈F₂O₃: C, 53.47; H, 3.99. Found: C, 53.40; H,3.89.

Step C—Preparation of S-(+)-3.5-Difluoromandelic acid

[1644] A solution of methyl S-(+)-3,5-difluoromandelate (1 eq.) in 74%aqueous THF was cooled to 0° C. and treated with lithium hydroxide.After 40 minutes at 0° C. the reaction was complete by TLC. The contentswere transferred to a separatory funnel and partitioned between CH₂Cl₂and saturated aqueous NaHCO₃. The aqueous layer was acidified with 0.5 NNaHSO₄ and extracted thrice with ethyl acetate. The combined extractswere washed with brine, dried over Na₂SO₄, filtered, and concentrated toa white solid having a melting point of 119-122° C. The ¹H NMR wasconsistent with known 3,5-difluoromandelic acid.

Example M Synthesis of 2-Azido-(3,5-difluorophenyl)acetic Acid

[1645] Step A: To a three-necked flask equipped with a mechanicalstirrer and a nitrogen inlet tube was added 3,5-difluorophenylaceticacid and THF. The reaction mixture was cooled to −78° C. and 1.2 eq. oftriethylamine was added, followed by dropwise addition oftrimethylacetyl chloride (1.05 eq.). During the addition, thetemperature was maintained at −78° C. The cold bath was then removed andreplaced with an ice bath. The temperature was allowed to warm to 0° C.and stirring was continued for 1 hour. The reaction mixture was thenre-cooled to −78° C. To a second flask charged with THF,triphenylmethane (cat, 0.1 mole %) and (S)-(−)-4-benzyl-2-oxazolidione(1.1 eq.) (Aldrich) at −78° C. was added an n-butyl lithium solutiondropwise until an orange color persisted. This reaction mixture wasstirred at −78° C. for 30 min. and then cannulated into the firstreaction mixture. The resulting mixture was allowed to stir at −78° C.for 1 hour and then quenched with 2.2 eq. of acetic acid. The solventwas removed under reduced pressure and the residue was redissolved indichloromethane and this solution washed with water, followed by 1Mpotassium carbonate. The organic layer was then dried over sodiumsulfate, filtered and concentrated. The residue was purified by LC 2000chromatography, eluting with EtOAC/Hexane (15:85). The resulting oil wasslurried in hexane to afford a white solid which was collected byfiltration to give(S)-(−)-3-(3,5-difluorophenyacetyl)-4-benzyl-2-oxazolidione.

[1646] Step B: To(S)-(−)-3-(3,5-difluorophenyacetyl)-4-benzyl-2-oxazolidione (3.0 mM) in20 mL of dry THF cooled to −78° C. was added LiHMDS (1.05 eq.) dropwisewhile maintaining the temperature at −78° C. The reaction mixture wasallowed o stir at −78° C. for 15 min. and then a pre-cooled (−60° C.)solution of trisyl azide (1.12 eq.) in 10 mL of THF was added. Thereaction mixture was allowed to stir an additional 10 min. and then wasquenched with 4.4 eq. of acetic acid. Using a warm water bath, thetemperature was raised to 30-40° C. for 6 hrs. The reaction mixture wasthen poured into a separatory funnel and extracted into dichloromethane.The organic layer was washed with bicarbonate solution, followed bybrine, and then dried over sodium sulfate, filtered and solvent removed.The residue was purified by LC 2000 chromatography to afford methyl2-azido-2-(3,5-difluorophenyl)acetate.

[1647] Step C: To a solution of methyl2-azido-2-(3,5-difluorophenyl)acetate in THF/H₂O (2.6:1) cooled to 0° C.was added 1.7 eq. of lithium hydroxide. The reaction mixture was stirredat room temperature for 3 hours and then poured into a separatoryfunnel. The mixture was extracted into water and washed with ether. Theaqueous layer was acidified with 1N HCl and extracted with ethylacetate. The organic layer was then washed with water and brine. Theorganic layer was dried over sodium sulfate, filtered and concentratedunder reduced pressure to give 2-azido-2-(3,5-difluorophenyl)aceticacid.

Example N Synthesis of (R)-N,N′-Di-BOC-2-Hydrazinopropionic Acid

[1648] Step A: To (S)-(−)-4-benzyl-2-oxazolidanone (Aldrich) in THFcooled to −50° C. was added n-butyl lithium 1.1 eq. (1.6 M in hexane)dropwise. The reaction mixture was allowed to warm to −20° C. and thenwas re-cooled to −78° C. and propionyl chloride (1.1 eq) was added inone portion. The reaction mixture was allowed to stir an additional 15min. at −78° C. and then was allowed to warm to room temperature. Thereaction was then quenched with a saturated solution of sodiumbicarbonate and extracted with ethyl acetate. The organic extracts werewashed with water, followed by brine and then dried over sodium sulfate,filtered and concentrated to give(S)-(−)-3-propionyl-4-benzyl-2-oxazolidanone.

[1649] Step B: To a solution of(S)-(−)-3-propionyl-4-benzyl-2-oxazolidanone in THF at −78° C. was addedKHMDS (1.05 eq.) (Aldrich) dropwise. The reaction mixture was allowed tostir at −78° C. for 30 min. and then a precooled solution ofdi-tert-butyl-azodicarboxylate (Aldrich) was added via a cannula. After5 min. 2.6 eq. of acetic acid was added. The reaction mixture was thenextracted with dichloromethane and the organic layer was washed with 1Mpotassium phosphate. The organic layer was then dried over sodiumsulfate, filtered and concentrated to give(S)-(−)-3-[(R)-N,N′-di-BOC-2-hydrazinopropionyl]-4-benzyl-2-oxazolidanone.

[1650] Step C: To(S)-(−)-3-[(R)-N,N′-di-BOC-2-hydrazinopropionyl]-4-benzyl-2-oxazolidanone(0.49 moles) at 0° C. in 8 mL of THF and 3 mL of water was added LiOH(1.7 eq.) and H₂O₂ (3.0 eq.) and the reaction mixture was stirred atroom temperature for 3 hours. The reaction mixture was then poured intoa separatory funnel and diluted with water. The aqueous mixture wasextracted with ethyl acetate and then acidified to pH 2.0 with 1N HCland extracted with ethyl acetate. The organic layer was then dried oversodium sulfate, filtered and solvent removed to give(R)-N,N′-di-BOC-2-hydrazinopropionic acid which was used without furtherpurification.

Example O Synthesis of 3,5-Difluorophenyl-α-oxoacetic Acid

[1651] Step A: Ethyl 3,5-difluorophenyl-α-oxoacetate was prepared from1-bromo -3,5-difluorobenzene (Aldrich) according to the proceduredescribed in J. Org. Chem., 45 (14), 2883-2887 (1980).

[1652] Step B: Ethyl 3,5-difluorophenyl-α-oxoacetate was hydrolyzedusing General Procedure II-A (Method B) to afford3,5-difluorophenyl-α-oxoacetic acid.

Example P Synthesis of Cyclopentyl-α-hydroxyacetic Acid

[1653] The title compound (CAS No. 6053-71-0) was prepared in two stepsfrom cyclopentylmethanal (CAS No. 872-53-7, Wiley) using the proceduredescribed by Gibby, W. A.; Gubler, C. J. Biochemical Medicine 1982, 27,15-25.

Example Q Synthesis of N-(3,4-dichlorophenyl)alanine

[1654] Using the procedure set forth in U.S. Pat. No. 3,598,859, thedisclosure of which is incorporated herein by reference in its entirety,N-(3,4-dichlorophenyl)alanine was prepared. Specifically, to a solutionof 3,4-dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mLper mL of isopropanol) and 2-chloropropionic acid (2 equivalents)(Aldrich). This mixture is warmed to 40° C. and sodium bicarbonate (0.25equivalents) is added in successive portions before heating under refluxfor 4-5 days. After cooling, the reaction mixture is poured into waterand the unreacted 3,4-dichloroaniline is removed by filtration. Thefiltrate is acidified to pH 3-4 with concentrated hydrochloric acid andthe resultant precipitate is filtered, washed and dried to yield thetitle compound, m.p.=148-149° C.

Example R Synthesis of N-(3,5-difluorophenyl)alanine

[1655] Using the procedure set forth in U.S. Pat. No. 3,598,859 andExample Q above, N-(3,5-difluorophenyl)alanine was prepared using3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).

Example S Synthesis of α-Fluoro-3,5-difluorophenylacetic Acid StepA—Synthesis of Methyl 3,5-Difluoromandelate

[1656] To a solution of 3,5-difluoromandelic acid (Fluorochem) inmethanol was bubbled HCl gas for 10 minutes. The reaction was refluxedovernight. The mixture was then concentrated in vacuo and the residuewas taken up in ethyl acetate and washed with saturated NaHCO₃ andbrine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated to give the title intermediate as a white solid.

[1657] C₉H₈F₂O₃ (MW=202.17); mass spectroscopy 202.

[1658]¹H NMR (300 MHz, CDCl₃): δ=7.00 (2H, d, J=6.58 Hz), 6.76 (1H, t,J=8.86 Hz), 5.16 (1H, d, J=5.29 Hz), 3.81 (3H, s), 3.54 (1H, d, J=5.39Hz).

Step B—Synthesis of Methyl α-Fluoro-3,5-difluorophenylacetate

[1659] A solution of diethylaminosulfur trifluoride (DAST) (1.1 eq) inmethylene chloride was cooled to 0° C. and a pre-cooled solution ofmethyl 3,5-difluoromandelate (1 eq) in methylene chloride was added. Thetransfer flask was rinsed with a small portion of methylene chloride.After 15 minutes, the cooling bath was removed and the reaction mixturewas stirred an additional 40 minutes at ambient temperature. The mixturewas poured over ice and the layers separated. The organic phase waswashed with saturated NaHCO₃ and brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated. The residue was purified via HPLCeluting with 7% ethyl acetate/hexanes providing the title intermediateas a yellow oil.

[1660] C₉H₇F₃O₂ (MW=204.16); mass spectroscopy 204.

[1661] Anal. calcd for C₉H₇F₃O₂: C, 52.95; H, 3.46. Found: C, 52.80; H,3.73.

Step C—Synthesis of α-Fluoro-3,5-difluorophenylacetic Acid

[1662] Following General Procedure II-A, Method B and using methylα-fluoro-3,5-difluorophenylacetate, the title intermediate was preparedas a white solid having a melting point of 100-102° C.

[1663] C₈H₅F₃O₂ (MW=190.13); mass spectroscopy 190.

[1664] Anal. calcd for C₈H₅F₃O₂: C, 50.54; H, 2.65. Found: C, 50.47; H,2.79.

[1665] III. Cycloalkyl, Lactam. Lactone and Related Compounds

[1666] 1. Cycloalkane Derivatives

Example 1-1 Synthesis of1-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-aminodibenzosuberane

[1667] Following General Procedure C above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and1-aminodibenzosuberane, the title compound was prepared. The product waspurified by chromatography (silica, 2.5% MeOH/CHCl₃), followed byrecrystallization from n-chlorobutane/acetonitrile.

[1668] NMR data was as follows:

[1669]¹H-nmr (DMSO-d₆): δ=4.53 (m, 1H), 6,37 (d, 1H).

[1670] C₂₆H₂₄N₂O₂F₂ (MW=434.48); mass spectroscopy (MH⁺) 434.

[1671] 2. Cyclic Alcohol Derivatives

Example 2-A Synthesis of5-Amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol Hydrochloride StepA—Synthesis of 5-Oximo-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one

[1672] A round bottom flask was charged with5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one (1.0 g, 4.81 mmol)(CAS#1139-82-8, prepared as described in Tetrahedron Letters, Vol. 28, No.23, (1987), pp 2633-2636) and butyl nitrite (0.673 ml, 5.77 mmol)(Aldrich) in Et₂O. The solution was cooled to 0° C. and treateddrop-wise with a saturated solution of HCl(g)/Et₂O. After 5 h at 0° C.the resulting precipitate was filtered, rinsed with cold Et₂O and vacuumdried to give the title compound as a colorless solid.

[1673] NMR data was as follows:

[1674]¹H-nmr (CDCl₃): δ=7.26-7.74 (m, 8H), 3.84 (m, 2H).

[1675] C₁₅H₁₁NO₂ (MW=237.26); mass spectroscopy (MH+) 238.

[1676] Anal. Calcd for C₁₅H₁₁NO₂; C, 75.93 H, 4.67 N, 5.90. Found: C,75.67 H, 4.83 N, 5.67.

Step B—Synthesis of 5-Amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-olHydrochloride

[1677] The compound isolated above (0.489 g, 2.04 mmol) was dissolved inTHF and added drop-wise to a well-stirred mixture of LAH (10.2 ml, 10.2mmol)/THF. After heating to reflux for 25 h under N₂ atmosphere thesolution was quenched and worked-up according to Fieser's method. Theresulting solid was rinsed with NH₃ sat/CHCl₃, the filtrate evaporatedand the title compound purified by chromatography (SiO₂, CHCl₃).

[1678] C₁₅H₁₅NO (MW=225.290); mass spectroscopy (MH+) 226.

[1679] Anal. Calcd for C₁₅H₁₅NO; C, 79.97 H, 6.71 N, 6.22. Found: C,80.19 H, 6.71 N, 5.91.

Example 2-1 Synthesis of1-(R)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-2-(S)-indanol

[1680] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and1-(R)-amino-2-(S)-indanol, the title compound was prepared.

Example 2-2 Synthesis of1-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-2-(R)-indanol

[1681] Following the General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and1-(S)-amino-2-(R)-indanol, the title compound was prepared.

Example 2-3 Synthesis of1-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-2-indanol

[1682] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and1-amino-2-indanol, the title compound was prepared.

Example 2-4 Synthesis oftrans-2-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-1-cyclohexanol

[1683] Following General Procedure C above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) andtrans-2-aminocyclohexanol hydrochloride (Aldrich), the title compoundwas prepared as a solid having a melting point of 189-191° C. Thereaction was monitored by tlc on silica gel (Rf=0.85 in 9%methanol/dichloromethane) and purification was by flash chromatographyusing 9% methanol/dichloromethane as the eluant.

[1684] NMR data was as follows:

[1685]¹H-nmr (CD₃OD): δ=6.8-6.6 (m, 3H), 4.1 (m, J=7.2 Hz, 1H), 3.4 (m,4H), 3.1 (m, 1H), 1.8-1.4 (m, 4H), 1.1 (m, 7H).

[1686]¹³C-nmr (CD₃OD) δ=175.4, 173.0, 113.9, 113.6, 103.9, 103.6, 74.3,56.9, 51.4, 51.4, 50.4, 43.4, 43.3, 43.31, 36.0, 35.5, 32.9, 32.8, 26.2,26.2, 25.9, 25.8, 18.8, 18.7.

[1687] C₁₇H₂₂N₂O₃F₂ (MW=340.37); mass spectroscopy (MH⁺) 341.

Example 2-5 Synthesis of1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1,2,3,4-tetrahydro-2-naphthol

[1688] Following General Procedure C and using usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and1-amino-1,2,3,4-tetrahydro-2-naphthol, the title compound was prepared.

Example 2-6 Synthesis of1-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-aminobenz[f]cycloheptan-2-ol

[1689] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) andcis-1-amino-2-hydroxybenzosuberane (prepared using the proceduredescribed in C. H. Senanayake et al., Tetrahedron Lett. (1995) 36(42),7615-7618), the title compound was prepared. The reaction was monitoredby tlc on silica gel (Rf=0.4 in 10% methanol/dichloromethane) andpurification was by silica gel chromatography using 10%methanol/dichloromethane as the eluant.

[1690] NMR data was as follows:

[1691] Mixture of cis isomers:

[1692]¹H-nmr (DMSO-d₆): δ=4.46 (m, 1H), 5.05 (d, 1H).

[1693] C₂₂H₂₃N₂O₃F₂ (MW=402.44); mass spectroscopy (MH⁺) 402.

[1694] Using the above procedure, followed by crystallization fromacetonitrile gave a single isomer:

[1695]¹H-nmr (DMSO-d₆): δ=4.46 (m, 1H), 5.03 (d, 1H).

[1696] C₂₂H₂₃N₂O₃F₂ (MW=402.44); mass spectroscopy (MH⁺) 402.

Example 2-7 Synthesis of5-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol

[1697] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and5-amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol hydrochloride(Example 2-A), the title compound was prepared as a colorless solid. Theproduct was purified by flash chromatography using 98:2 CHCl₃/MeOH.

[1698] C₂₆H₂₄F₂N₂O₃ (MW=450.48); mass spectroscopy (MH+) 451.

[1699] Anal. Calcd for C₂₆H₂₄F₂N₂O₃; C, 69.32 H, 5.37 N, 6.22. Found: C,69.02 H, 5.53, N, 6.34.

[1700] 3. Cyclic Ketone Derivatives

General Procedure 3-A Jones Oxidation Procedure

[1701] The compound to be oxidized was stirred in acetone and the Jonesreagent was added in portions until the starting material was consumed.The reaction mixture was quenched with isopropanol and the mixture wasfiltered through Celite and concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and water and the organicportion was dried over sodium sulfate and then concentrated underreduced pressure. The crude product was purified by silica gelchromatography and/or recrystallization.

General Procedure 3-B Swern Oxidation Procedure

[1702] To a stirred mixture of oxalyl chloride (0.1.5 mL, 1.2 mmol) in10 mL of dichloromethane cooled to −78° C. was added DMSO (0.106 mL, 1.5mmol) and the mixture was stirred for 10 minutes. A solution of thalcohol (0.1828 g, 0.60 mmol) in 20 mL of chloroform was added dropwise.The reaction mixture was stirred at −78° C. for 2 hours, and then 0.5 mL(3.6 mmol) of triethylamine was added. Stirring was continued for 1 hourand then the mixture was allowed to warm to room temperature andstirring was continued at ambient temperature overnight. The mixture wasthen diluted with 50 mL of dichloromethane, washed with brine (3×),dried over magnesium sulfate, filtered and evaporated to dryness to givethe crude product which as typically purified by column chromatography.

Example 3-1 Synthesis of1-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-aminoindan-2-one

[1703] Following General Procedure 3-A using the product from Example2A-2, the title compound was prepared as a solid having a melting pointof 221-224° C. The reaction was monitored by tlc on silica gel (Rf=0.4in 15% methanol/dichloromethane) and purification was by silica gelchromatography using 5% methanol/dichloromethane as the eluant, followedby recrystallization from 1-chlorobutane/acetonitrile.

[1704] NMR data was as follows:

[1705]¹H-nmr (DMSO-d₆): δ=1.25 (d, 3H), 4.34 (m, 1H), 5.22 (d, 1H), 8.37(d, 1H), 8.72 (d, 1H).

[1706] C₂₀H₁₈N₂O₃F₂ (MW=372.38); mass spectroscopy (M⁺) 372.34.

Example 3-2 Synthesis of2-(N′-(Phenylacetyl)-L-alaninyl)aminocyclohexan-1-one

[1707] Following General Procedure 3-B above using2-(N′-(phenylacetyl)-L-alaninyl)-amino-1-cyclohexanol (Example 2-4), thetitle compound was prepared as a solid having a melting point of150-157° C. Purification was by silica gel chromatography using 3%methanol/dichloromethane as the eluant.

[1708] NMR data was as follows:

[1709]¹H-nmr (CDCl₃): δ=7.24-7.40 (m, 5H), 6.7-6.9 (m, 1H), 6.1 (m, 1H),4.5 (m, 1H), 4.40 (m, 1H), 3.61 (s, 2H), 3.59 (s, 2H), 2.55 (m, 2H),2.38 (m, 1H0, 2.13 (m, 1H0, 1.72-1,92 (m, 2H), 1.63 (m, 1H), 1.32 (m,4H).

[1710]¹³C-nmr (CDCl₃) δ=207.3, 171.75, 171.69, 170.8, 170.6, 134.6,134.5, 129.3, 129.2, 128.9, 127.3, 127.2, 57.93, 57.88, 48.8, 48.7,43.5, 40.99, 40.96, 35.0, 34.8, 27.8, 23.96, 23.92, 18.7, 18.4.

[1711] C₁₇H₂₇N₃O₃ (MW=302.38).

Example 3-3 Synthesis of5-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one

[1712] Using General Procedure 3-A and using5-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol(Example 2-7), the title compound was prepared. The product was purifiedby flash chromatography using 97:3 CHCl₃/MeOH.

[1713] NMR data was as follows:

[1714]¹H-nmr (CDCl₃): δ=7.61-7.16 (m, 8H), 6.78 (m, 2H), 6.69 (m, 1H),6.31 and 6.21 (two d, 1H), 5.51 (d, 1H), 4.67 (m,1H), 3.66 (m, 2H), 3.49(two s, 2H), 1.49 and 1.38 (two m, 3H).

[1715] C₂₆H₂₂F₂N₂O₃ (MW=448.46); mass spectroscopy (MH+) 449.

[1716] Anal. Calcd for C₂₆H₂₂F₂N₂O₃; C, 69.63 H, 4.94 N, 6.25. Found: C,69.67 H, 4.85, N, 6.23.

Example 3-4 Synthesis of1-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-aminobenz[f]cycloheptan-2-one

[1717] Following General Procedure 3-A and using1-(N′-(3,5-difluorophenyl-acetyl)-L-alaninyl)-aminobenz[f]cycloheptan-2-ol(Example 2-6), the title compound was prepared.

[1718] 4. Lactones

Example 4-1 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-γ-butyrolactone

[1719] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) andα-amino-γ-butyrolactone hydrobromide (Aldrich), the title compound wasprepared as a solid having a melting point of 174-177° C. The reactionwas monitored by tlc on silica gel (Rf=0.52 in 10%methanol/dichloromethane) and purification was by silica gelchromatography.

[1720] NMR data was as follows:

[1721]¹H-nmr (CDCl₃): δ=8.4 (m, 2H), 7.1 (m, 1H); 7.0 (m, 2H); 4.6 (m,1H); 4.4 (m, 2H); 3.52 (s, 2H); 2.2 (m, 2H); 1.22 (m, 3H).

[1722]¹³C-nmr (CDCl₃): δ=175.6, 172.7, 169.2, 112.8, 106.6, 102.2, 65.6,48.5, 48.3, 41.6, 28.6, 18.7.

[1723] C₁₅H₁₆F₂N₂O₄ (MW=326); mass spectroscopy (MH⁺) 327.

Example 4-2 Synthesis of3-(N′-(3,4-dichlorophenyl)-D,L-alaninyl)amino-γ-butyrolactone

[1724] Following General Procedure A and usingN-(3,4-dichlorophenyl)-D,L-alanine (Example A) andα-amino-γ-butyrolactone hydrobromide (Aldrich), the title compound wasprepared. The reaction was monitored by tlc on silica gel (Rf=0.19 in60% EtOAc/hexane) and purification was by silica gel chromatographyusing 60% EtOAc/hexanes as the eluent.

[1725] NMR data was as follows:

[1726]¹H-nmr (CDCl₃): δ=1.56 (d, J=7 Hz, 3H), 2.0-2.15 (m, 1H), 2.75-2.9(m, 1H), 3.75-3.90 (m, 1H), 4.0 (brs, 1H), 4.2-4.35 (m, 1H), 4.45 (t,J=7, 1H), 4.5-4.7 (m, 1H), 6.4-6.5 (m, 1H), 6.67 (d, J=3 Hz, 1H),7.0-7.1 (m, 1H), 7.2-7.3 (m, 1H).

[1727]¹³C-nmr (CDCl₃): δ=20.0, 30.7, 49.4, 55., 66.5, 113.7, 115.5,112.8, 131.5, 133.7, 146.3, 174.5, 175.5.

[1728] C₁₃H₁₄C₂N₂O₃ (MW=317.17); mass spectroscopy (M⁺) 317.

Example 4-3 Synthesis of4-(N′-(Cyclopentylacetyl)-L-alaninyl)amino-1,1-dimethyl-3-isochromanone

[1729] Following General Procedure A above usingN-(cyclopentylacetyl)-L-alanine and4-amino-1,1-dimethyl-3-isochromanone, the title compound could beprepared.

Example 4-4 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,1-dimethyl-3-isochromanone

[1730] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine and4-amino-1,1-dimethyl-3-isochromanone, the title compound could beprepared.

[1731] 5. Lactams

General Procedure 5-A N-Alkylation of Lactams

[1732] To a stirred solution of a BOC-protected α-aminocaprolactam (6.87g, 30 mmol) in DMF (150 mL) was added in portions 97% NaH (1.08 g, 45mmol). Bubbling occured immediately and followed by heavy precipitation.After 10 min., benzyl bromide (3.93 mL, 33 mmol) was added. Theprecipitate dissolved quickly and in about 10 min. a clear solution wasobtained. The reaction mixture was stirred overnight and then evaporatedas completely as possible on a rotovap at 30° C. Ethyl acetate (100 mL)was added to the residue and this mixture was washed with water, brine,and dried over magnesium sulfate. After filtration and concentration, athick liquid (10 g) was obtained which was then chromatographed oversilica gel with 1:3 ethyl acetate/hexane as the eluant to provide 5.51 g(58%) of the N-benzylated product as an oil. Other lactams andalkylating agents may be used in this procedure to obtain a wide varietyof N-alkylating agents may be used in this procedure to obtain a widevariety of N-alkylated lactams. Various bases, such as LiN(SiMe₃), mayalso be employed.

General Procedure 5-B BOC Removal Procedure

[1733] The BOC-protected compound in a 1:1-2:1 mixture of CH₂Cl₂ and 2hours. The solution was then stripped to dryness and the residue wastaken up in ethyl acetate or CH₂Cl₂. The solution was washed withsaturated aqueous NaHCO₃ and the aqueous phase was adjusted to a basicpH, then extracted with ethyl acetate or CH₂Cl₂. The organic phase waswashed with saturated aqueous NaCl and dried over MgSO₄. The solutionwas stripped free of solvent on a rotary evaporator to yield theproduct.

General Procedure 5-C Synthesis of α-Aminolactams

[1734] The Schmidt reaction was conducted on 4-ethylcyclohexanone usinghydroxyamine sulfonic acid as described in Olah, Org Synth. Collective,Vol. VII, page 254, to provide 5-ethylcaprolactam in 76% yield. Usingthe procedure described in Watthey, et al., J. Med. Chem., 1985, 28,1511-1516, this lactam was then dichlorinated with PCl₅ at the alphaposition and reduced by hydrogenation to provide four isomericmonochlorides (two racemic mixture). The two racemic mixtures wereseparated from each other by column chromatography using silica gel andeach racemic mixture was reacted with sodium azide to yield thecorresponding azide which was hydrogenated to provide the correspondingα-aminolactans. Other cycloalkanones may be employed in this procedureto provide a wide variety of α-aminolactams. In some cases, such as whenpreparing the 9-membered ring α-aminolactam, longer reaction times,higher reaction temperatures and an excess of sodium azide may berequired. For example, the 9-membered ring α-aminolactam required 5equivalents of sodium azide, a reaction temperature of 120° C. and areaction time of 4 days. Such conditions can be readily determined bythose of ordinary skill in the art.

General Procedure 5-D Synthesis of4-Amino-1.2,3,4-tetrahydroisoquinoline-3-ones

[1735] The 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivativesemployed in this invention can be prepared by the followingart-recognized procedures. The conditions for these reactions arefurther described in D. Ben-Ishai, et al., Tetrahedron, 43, 439-450(1987). The following intermediates were prepared via this procedure:

[1736] 3-amino-1,2,3,4-tetrahydroisoquinolin3-one

[1737] 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1738] 4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1739] cis andtrans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1740] 4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1741] 4-amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1742] 9-amino(fluoren-1-yl)glycineδ-lactam-1,2,3,4-tetrahydroisoquinolin-3-one.

[1743] Step A—Preparation of N-Bismethoxycarbonylaminoacetic Acid: Toone mole equivalent of glyoxylic acid in 2 liters of ethanol-freechloroform was added two mole equivalents of methyl carbamate and 0.1mole equivalent of naphthalene sulfonic acid. The reaction mixture wasthen brought to a reflux for 6 hours. Water was removed using an inverseDean Stark trap. The reaction was then cooled and the product filteredand washed with chloroform. The white solid was recrystallized fromethyl acetate/hexanes to give a white powder in 65% yield.

[1744] Step B—Coupling Procedure: To 0.0291 moles ofN-bismethoxycarbonylaminoacetic acid (or the appropriate carboxcyclicacid) in 200 mL of THF was added one mole equivalent of EDC.HCl, abenzylamine, HOBT, and diisopropylethylamine. The reaction was allowedto stir at room temperature for 18 hours and then poured into aseparatory funnel and extracted into ethyl acetate. The ethyl acetatesolution was washed with 1 molar K₂CO₃ and then 1 molar HCl. The organiclayer was dried over Na₂SO₄, filtered and solvent removed to give thecrystalline benzylamide of N-bismethoxycarbonylaminoacetic acid. Thismaterial was used without further purification. Typical yields rangefrom 40-55%.

[1745] Step C—Cyclization Procedure: The benzylamide ofN-bismethoxycarbonylaminoacetic acid (0.008 moles) was dissolved in 75mL of methanesulfonic acid and allowed to stir over night at roomtemperature. The reaction mixture was poured over ice and extracted intoethyl acetate. The ethyl acetate extract was washed with 1 molar K₂CO₃and then 1 N HCl. The organic layer was dried over Na₂SO₄, filtered andthe solvent removed to give the crystalline4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one in 50-90%yield. This material was used without further purification.

[1746] Step D—Removal of the Methoxyoxycarbonyl Grout (MOC): To the4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles)in 30 mL of acetonitrile was added 2 mole equivalents oftrimethylsilyliodide (TMSI). The reaction mixture was heated to 50-80°C. for 3 hrs and then cooled and poured into a seperatory funnel. Thereaction mixture was diluted with ethyl acetate and washed with 1 molarK₂CO₃ and then with 5% NaHSO₃. The organic layer was dried over Na₂SO₄and filtered. The solvent was removed under reduced pressure to give the4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yieldsrange from 50-87%.

[1747] Step E—Alternative Procedure for Removal of theMethoxyoxycarbonyl Group: To 3.8 mmoles of the MOC-protected compoundwas added 10 mL of 30% HBr in acetic acid and this reaction mixture washeated to 60° C. for 3 hrs. The mixture was then cooled and hexanes wereadded. The hexanes layer was decanted off and the residue as placedunder reduced pressure to give a tan solid. This solid was slurried inether and filtered to give the4-amino-1,2,3,4-tetrahydroisoquinoline-3-one hydrobromide salt. Typicalyields range from 57-88%.

Example 5-A Synthesis of 3-Amino-1,2,3,4-tetrahydroquinolin-2-one

[1748] Step A: Sodium (0.30 g, 110M %) was added to anhydrous ethanol(45 mL) and the reaction mixture was stirred until homogenous. DiethylN-acetylaminomalonate (2.51 g, 100 M %) was added in one portion andthis mixture was stirred for 1 h. 2-Nitrobenzyl bromide (2.5 g, 100 M %)was then added in one portion and the reaction mixture was stirred for 3h. The reaction was poured into water and extracted with ethyl acetate(3×) and then backwashed with water (3×) and brine (1×). Treatment withMgSO₄, rotoevaporation, and chromatography (30% EtOAc/hexanes) yieldeddiethyl N-acetylamino-2-nitrobenzylmalonate in 82% yield.

[1749] Step B: Diethyl N-acetylamino-2-nitrobenzylmalonate (1 g, 100M %)was dissolved in a minimum amount of EtOH. Pd/C (10%, 0.05 g) was addedand the reaction mixture was subjected to 50 psi of H₂ for 3 hours. Thereaction was then filtered thru a pad of celite. Additional EtOH (25 mL)and TsOH (catalytic amount, 0.01 g) were added and this mixture wasrefluxed for 2 hours. The reaction was rotoevaporated to a residue andthen partitioned between water and ethyl acetate. The water layer wasextracted with ethyl acetate (3×) and the combined ethyl acetateextracts were washed with water (3×) and then brine (1×). Treatment withMgSO₄ and rotoevaporation yielded pure3-(N-acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (89%yield).

[1750] Step C:3-(N-Acetylamino)-3-carboethoxy-1,2,3,4-tetrahydroquinolin-2-one (0.75g, 100M %) was suspended in 6N HCl (25 mL) and the mixture was heated to100° C. for 3 hours. The reaction was cooled, rotoevaporated to aresidue and then partitioned between water and ethyl acetate. The waterwas extracted with ethyl acetate (3×) and the combined ethyl acetateextracts were then washed with water (3×) and then brine (1×). Treatmentwith MgSO₄ followed by rotoevaporation yielded3-(R,S)-amino-1,2,3,4-tetrahydroquinolin-2-one (72% yield).

Example 5-B Synthesis of4-Amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

[1751] Step A: To a solution of 4-cyanopyridine (Aldrich) (0.150 moles)in 300 mL of dry ether was added 1.1 eq. of phenylmagnesium bromide(Aldrich) dropwise. The reaction was refluxed for 2 hours and thenstirred overnight at room temperature. Sodium borohydride (1.0 eq.) wasadded dropwise as a solution in 200 mL of methanol (CAUTION—veryexothermic). The reaction was then heated to reflux for 6 hours, cooledand quenched with a saturated solution of ammonium chloride. Thesolution was decanted from the salt in the reaction mixture andacidified with 1N HCl. After washing the aqueous layer with ethylacetate, the pH of aqueous layer was adjusted to about 9.0 with 1Nsodium hydroxide (cold). The aqueous layer was then extracted with ethylacetate and the organic extracts washed with brine, dried over Na₂SO₄,filtered and concentrated to give 4-pyridyl-α-benzyl amine as a thickyellow oil.

[1752] Step B: Following General Procedure 5-D and using4-pyridyl-α-benzyl amine, the title compound was prepared.

Example 5-C Synthesis of4-Amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

[1753] Step A: 2-Pyridyl-α-benzyl amine was prepared by substituting2-cyanopyridine (Aldrich) for 4-cyanopyridine in the procedure describedin Example 5-B.

[1754] Step B: Following General Procedure 5-D and using4-pyridyl-α-benzyl amine, the title compound was prepared.

Example 5-D Synthesis of4-Amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

[1755] Step A: Following the procedure described in J. Med. Chem., 1982,25, 1248, and using 3-benzoyl-pyridine (Aldrich), 3-pyridyl-α-benzylamine was prepared.

[1756] Step B: Following General Procedure 5-D and using3-pyridyl-α-benzyl amine, the title compound was prepared.

Example 5-E Synthesis of4-Amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1757] Step A: To a Parr bottle containing 3-benzoylbenzoic acid (0.044moles) (Aldrich) in 150 mL of ethyl acetate and 4.5 mL of concentratedH₂SO₄ was added 10 grams of 5% Pd/C. The mixture was hydrogenated on aParr apparatus under hydrogen (45 psi) overnight. The reaction mixturewas then filtered through Hyflo, washing with ethyl acetate. Thefilterate was dried over Na₂SO₄, filtered and concentrated to give anoil. The oil was slurried in hexane and the resulting white solid wascollected by filtration to afford 3-benzylbenzoic acid, which was usedwithout further purification.

[1758] Step B: To the product from Step A (0.0119 moles) was added 150mL of CH₂Cl₂, one drop of DMF, 10 mL of oxalyl chloride, and the mixturewas stirred at room temperature for 3 hours. After cooling to 10° C., 30mL of NH₄OH (exothermic) was added and the mixture was stirred for 30min. The reaction mixture was then concentrated and the resultingresidue diluted with ethyl acetate. The organic layer was washed with 1NNaOH, brine, dried over Na₂SO₄, and concentrated to give the3-(benzyl)benzamide as a white solid, which was used without furtherpurification.

[1759] Step C: To a solution of 3-(benzyl)benzamide (0.0094 moles) fromStep B in 70 of toluene was added 8 mL of Red-Al® (65+wt. % solution ofsodium bis(2-methoxyethoxy)aluminum hydride in toluene, Aldrich)(CAUTION—reaction very exothermic). The reaction mixture was then heatedat 60° C. for 2 hours and then poured over ice. The resulting mixturewas extracted with ethyl acetate and the combined extracts were washedwith water and brine. The organic layer was extracted with 1N HCl andthe aqueous layer washed with ethyl acetate. The pH of the aqueous layerwas then adjusted to about 9.0 with 1N NaOH and extracted with ethylacetate. The organic extracts were washed with water and brine and thenconcentrated to give 3-(benzyl)benzyl amine.

[1760] Step D: Following General Procedure 5-D and using3-(benzyl)benzyl amine, the title compound was prepared.

Example 5-F Synthesis of4-Amino-6-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1761] Step A: To a solution of 4-biphenylcarboxamide (Aldrich) (0.025mole) in 150 mL of THF cooled to 10° C. was added a solution of 1.5 eqof LAH (1M in THF) dropwise. The reaction mixture turned from a whiteslurry to a green homogenous solution and then to a yellow homogeneoussolution. The reaction was then quenched with 2.5 mL of 1N NaOH. Themixture was then filtered through Hyflo and extracted with ethylacetate. The organic layer was then washed with 1N HCl. The pH of theresulting aqueous layer was adjusted to about 9 with 1N NaOH andextracted with ethyl acetate. The organic extracts were washed withwater and brine, and then dried over Na₂SO₄, filtered and concentratedto give 4-(phenyl)benzyl amine as a white solid.

[1762] Step B: Following General Procedure 5-D and using4-(phenyl)benzyl amine, the title compound was prepared.

Example 5-G Synthesis of cis- andtrans-4-Amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1763] Step A: Following General Procedure 5-D and usingα-phenylbenzylamine (Aldrich),4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one was prepared.

[1764] Step B: To a solution of4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one (0.00158 moles)from Step A in 20 mL of CH₂Cl₂ was added 2.0 eq. of triethylamine andBoc anhydride (1.1 eq.). The reaction was stirred overnight at roomtemperature and then concentrated. The residue was diluted with ethylacetate and water. The pH of the aqueous layer was adjusted to 3.0 withsodium bisulfate and the layers were separated. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby LC 2000, eluting with ethyl acetate/hexanes (70:30) to give a whitesolid containing a 1:1 mixture of cis- andtrans-4-(N-Boc-amino)-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-oneisomers. This mixture was recrystallized from ethyl acetate to give thepure trans isomer and a cis isomer-enriched mixture of cis and transisomers. This mixture was recrystallized again from ethylacetate/hexanees (70:30) to give the pure cis isomer.

[1765] Step C: The cis isomer and the trans isomer from Step B wereseparately deprotected using General Procedure 8-J to givecis-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one andtrans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one.

Example 5-H Synthesis of4-Amino-7-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1766] Step A: To a solution of 1-bromo-3-phenylbenzene (Aldrich)(0.0858 moles) in 300 mL of dry THF cooled to −78° C. was addedtert-butyl lithium (2 eq.) (1.7M in hexane) dropwise. The reactionmixture was stirred for 40 min. at −78° C. and then quenched with 2 eq.of DMF (13.24 mL). The resulting mixture was stirred for 20 min. andthen poured into a separatory funnel and extracted with CH₂Cl₂. Theorganic extracts were washed with water, dried over Na₂SO₄, filtered andconcentrated to give a brown oil. This oil was purified by LC 2000chromatography, eluting with ethyl acetate/hexanes (5:95) to give3-biphenylcarboxaldehyde.

[1767] Step B: To a solution of 3-biphenylcarboxaldehyde (0.011 eq.) in30 mL of methanol was added 10 eq. of 7N NH₃/MeOH and NaCNBH₄ (2 eq.). Ayellow gum precipitated from solution. The solution was then heated at60° C. until gum dissolved and the solution was stirred at roomtemperature overnight. The reaction mixture was then concentrated andthe resulting residue diluted with ice water and ethyl acetate. Theorganic layer was then washed with brine and extracted with 5N HCl. ThepH of the aqueous layer was then adjusted to 12 and the aqueous layerwas extracted with cold ethyl acetate. The organic layer was dried overNa₂SO₄, filtered and concentrated to give 3-(phenyl)benzyl amine as anoil.

[1768] Step C: Following General Procedure 5-D and using3-(phenyl)benzyl amine, the title compound was prepared.

Example 5-I Synthesis of4-Amino-1-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1769] Step A: To a solution of benzoyl chloride (0.123 moles) (Aldrich)in 600 mL of CH₂Cl₂ was added 2.0 eq. of phenethylamine (Aldrich)dropwise. The reaction mixture was stirred at room temperature for 3hours and then poured into a separatory and extracted with CH₂Cl₂. Theorganic extracts were washed with water and 1N HCl, and then dried overNa₂SO₄, filtered and concentrated to give N-phenethyl benzamide.

[1770] Step B: Reduction of N-phenethyl benzamide using the procedure ofExample 5-E, Step C afforded N-benzyl-N-phenethylamine as an oil.

[1771] Step C: Following General Procedure 5-D and usingN-benzyl-N-phenethylamine, the title compound was prepared.

Example 5-J Synthesis of 3-Amino-1-methyl-2-indolinone Monohydrochloride

[1772] Step A: (2,3-Dihydro-1-methyl-2-oxo-1H-indol-3-yl)carbamic acidmethyl ester (CAS No. 110599-56-9) was prepared using the proceduredescribed in Ben-Ishai, D.; Sataty, I.; Peled, N.; Goldshare, R.Tetrahedron 1987, 43, 439-450. The starting materials for thispreparation were N-methylaniline (CAS# 100-61-8, Eastman Kodak Co.),glyoxylic acid (CAS# 298-12-4, Aldrich), and methyl carbamate (CAS#598-55-0, Aldrich).

[1773] Step B: The product from Step A (333.5 mg) in 31% HBr in AcOH (10mL) was heated to 50-60° C. for 2 hours. The resulting orange solutionwas concentrated to a thick orange oil which was dissolved in EtOAc (15mL) and the product extracted into 1 M aq. HCl (10 mL). The aqueous acidwas neutralized with aq. NaHCO₃ and the product extracted into CH₂Cl₂(10×10 mL). HCl (gas) was passed through the combined CH₂Cl₂ extracts toform a purple solution. The solution was concentrated to provide thetitle compound (262.8 mg) as a purple solid.

Example 5-K Synthesis of3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/Tin Complex StepA:—Synthesis of 4-Phenyl-3,4-dihydrocarbostyril

[1774] 4-Phenyl-3,4-dihydrocarbostyril (CAS# 4888-33-9) was prepared intwo steps using the procedure described by Conley, R. T.; Knopka, W. N.J. Org. Chem. 1964, 29, 496-497. The starting materials for thispreparation were cinnamoyl chloride (Aldrich) and aniline (Aldrich). Thetitle compound was purified by flash chromatography eluting withCH₂Cl₂/EtOAc (4:1).

Step B:—Synthesis of 1-Methyl-4-phenyl-3,4-dihydrocarbostyril

[1775] To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion inmineral oil) in THF (50 mL) under N₂ at 0° C. was added the product fromStep A (1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5minutes. The resulting pale yellow mixture was stirred at 0° C. for 10minutes, then MeI (2.0 eq., 1.39 mL) was added. The opaque yellowmixture was allowed to slowly (ice bath not removed) warm to ambienttemperature with stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc(250 mL) were added and the phases partitioned. The organic phase waswashed with dilute NaHCO₃ (1×100 mL), brine (1×100 mL), then dried overMgSO₄, filtered, concentrated, and the residue purified by flashchromatography eluting with CH₂Cl₂/EtOAc (19:1 gradient to 15:1) toprovide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.

Step C:—Synthesis of3-Azido-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril

[1776] Following General Procedure 8-K,3-azido-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril was prepared as awhite solid. The product was purified by flash chromatography elutingwith CH₂Cl₂/hexanes/EtOAc 15:15:1.

[1777] Selected ¹H-NMR data for the title compound (CDCl₃): δ=4.46 (d,1H, J=10.57 Hz), 4.18 (d, 1H, J=10.63 Hz).

Step D:—Synthesis of3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril/Tin Complex

[1778] To a mixture of SnCl₂ (350.7 mg) in MeOH (7 mL) under N₂ at 0° C.was added the product from Step C (257.4 mg) in MeOH/THF (5 mL/5 mL) viacannula over a period of 1 minute. The cooling bath was removed thesolution allowed to warm to ambient temperature for 8 hours (No startingmaterial by TLC). The solution was concentrated to a yellow foam, THF(10 mL) was added and the mixture was re-concentrated and used withoutfurther purification.

Example 5-L Synthesis of3-Amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril Step A:—Synthesisof 3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril

[1779] 3-Amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril wasprepared following General Procedure 8-F using3-azido-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril from Example 5-K,Step C. The product was purified by L.C. 2000 eluting with EtOAc/hexanes(4:1) to yield a white solid.

[1780] Selected ¹H-NMR data for the title compound (CDCl₃): δ=4.03 (d,1H, J=12.8 Hz), 3.92 (d, 1H, J=12.7 Hz).

Step B:—Synthesis of3-(4-Chlorobenzylimine)-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril

[1781] To a solution of the product from Step A (1 eq., 239.6 mg) inCH₂Cl₂ (10 mL) under N₂ at ambient temperature was added4-chlorobenzaldehyde (1.05 eq., 140 mg, Aldrich), Et₃N (1.4 eq., 185mL), and MgSO₄ (3.6 eq., 411 mg). The resultant mixture was stirred atroom temperature for 73 hours. The solids were removed by filtrationthrough a plug of Celite, rinsing with CH₂Cl₂, and the filtrateconcentrated to provide3-(4-chlorobenzylimine)-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyrilas a thick white foam.

Step C:—Synthesis of3-Amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril

[1782] To a solution of diisopropylamine (1.05 eq., 0.132 mL) in THF (5mL) under N₂ at −78° C. was added a solution of n-BuLi (1.05 eq., 0.588mL of a 1.6 M solution in hexanes) and the result solution was stirredfor 30 minutes. To this solution was added the product from Step B (1.0eq., 336 mg) in THF (2 mL) via cannula. The solution was allowed to warmto 0° C., then quenched with 1 M aq. HCl (3 mL) and allowed to warm toroom temperature with stirring overnight. The product was extracted intoH₂O and washed with EtOAc (1×), then the aqueous acid was basified with1 M aq. K₂CO₃ and the product extracted into EtOAc. The EtOAc extractwas dried over Na₂SO₄, filtered, and concentrated to give3-amino-1-methyl-4-phenyl-3,4-cis-dihydrocarbostyril.

[1783] Selected ¹H-NMR data for the title compound (CDCl₃): δ=4.31 (d,1H, J=6.6 Hz).

Example 5-M Synthesis of3-Amino-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyril/TinComplex Step A:—Synthesis of1-tert-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyril

[1784] 1-tert-Butoxycarbonyl-4-phenyl-3,4-dihydrocarbostyril wasprepared from the product of Example 5-K, Step A (CAS# 4888-33-9) by theBoc procedure for aryl amides described by Grehn, L.; Gunnarsson, K.;Ragnarsson, U. Acta Chemica Scandinavica B 1986, 40, 745-750; employing(Boc)₂O (Aldrich) and catalytic DMAP (Aldrich) in acetonitrile. Theproduct was purified by flash chromatography eluting with CH₂Cl₂gradient to CH₂Cl₂/EtOAc (19:1) and isolated as a pale yellow oil.

Step B—Synthesis of3-Azido-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyril

[1785] Following General Procedure 8-K using the product from Step A,the title compound was prepared as a 12.4:1 mixture of trans/cis isomerswhich were separated by flash chromatography eluting with hexanes/Et₂O(6:1 gradient to 4:1) in the first column and hexanes/EtOAc (12:1) in asecond column. The pure trans isomer was used in Step C.

[1786] Selected ¹H-NMR data for the title compound (CDCl₃): δ=4.45 (d,1H, J=11.1 Hz), 4.24 (d, 1H, J=11.2 Hz).

Step C:—Synthesis of3-Amino-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyril/TinComplex

[1787] To a mixture of SnCl₂ (450.6 mg) in MeOH (9 mL) under N₂ at 0° C.was added the product from Part D (433.0 mg) in MeOH (15 mL) via cannulaover a period of 1 minute. The cooling bath was removed the solutionallowed to warm to ambient temperature for 17 hours. The solution wasconcentrated to an amorphous yellow solid and used without furtherpurification.

Example 5-N Synthesis of (S)-3-Amino-1-benzyl-δ-valerolactam StepA:—Synthesis of L-(+)-Ornithine Methyl Ester Hydrochloride

[1788] Into a stirred suspension of L-(+)-ornithine hydrochloride(Aldrich) in methanol was bubbled anhydrous hydrochloric acid gas untilthe solution was saturated. The reaction mixture was capped with arubber septum and stirring was continued overnight at room temperature.The solvent was then stripped under reduced pressure and the residuetriturated with ether. The resulting solid was dried under reducedpressure to afford L-(+)-ornithine methyl ester hydrochloride as a whitesolid (97% yield).

Step B:—Synthesis of (S)-3-Amino-δ-valerolactam

[1789] Sodium spheres in oil (2.0 eq.) (Aldrich) were washed withhexanes (2×) and methanol (2.3 mL/mmol) was slowly added. The reactionmixture was stirred under nitrogen until the sodium dissolved and thenL-(+)-ornithine methyl ester hydrochloride (1 eq.) in methanol (2.3mL/mmol) was added dropwise. The reaction mixture was stirred for 16hours and then diluted with diethyl ether (5 mL/mmol) and filtered toremove the solids. The solvent was then removed under reduced pressureand the residue was heated at 70° C. for 3 hours under reduced pressure.The residue was then triturated with dichloromethane/ether, the solventdecanted and the resulting residue dried under reduced pressure toafford (S)-3-amino-δ-valerolactam (44% yield).

Step C:—Synthesis of N-Boc-(S)-3-Amino-δ-valerolactam

[1790] (S)-3-Amino-δ-valerolactam (1 eq.) was dissolved in dioxane andthe solution was chilled to 0° C. BOC-anhydride (1.3 eq.) was added andthe ice bath was removed allowing the solution to come to roomtemperature and stirring was continued for 16 hours. The solution wasrotory evaporated to afford N-Boc-(S)-3-amino-δ-valerolactam.

Step D:—Synthesis of (S)-3-Amino-1-benzyl-δ-valerolactam

[1791] Following General Procedure 5-A and usingN-Boc-(S)-3-amino-δ-valerolactam and benzyl bromide providedN-Boc-(S)-3-amino-1-benzyl-δ-valerolactam. Removal of the Boc groupusing General Procedure 5-B afford the title compound.

Example 5-O Synthesis of4-Amino-2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane Hydrochloride StepA:—Synthesis of 2-Aza-3-oxobicyclo[3.2.1]octane and3-Aza-2-oxobicyclo[3.2.]octane (9:1 Mixture)

[1792] To (±)-norcamphor (Aldrich) in 1 mL/mmole of acetic acid wasadded 1.5 eq. of hydroylamine-O-sulfonic acid. The reaction mixture washeated to reflux under nitrogen for 1 hour and then saturated sodiumcarbonate and dilute sodium hydroxide were added. The resulting mixturewas extracted with dichloromethane and the organic extracts washed withbrine, dried over sodium sulfate, and the solvent removed under reducedpressure. Purification of the residue by column chromatography affordeda 9:1 mixture of 2-aza-3-oxobicyclo[3.2.1]octane and3-aza-2-oxobicyclo[3.2.1]octane.

Step B:—Synthesis of 2-Aza-2-benzyl-3-oxobicyclo[3.2.1]octane

[1793] Following General Procedure 5-A and using the product for Step Aand benzyl bromide, 2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane wasprepared.

Step C:—Synthesis of 2-Aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane

[1794] To a solution of 2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane in THFwas added 2.5 eq. of 1M t-BuOK/THF (Aldrich) and the resulting mixturewas stirred for 30 minutes. Isoamyl nitrite (1.5 eq.) was then addeddropwise and the reaction mixture was stirred overnight. To the reactionmixture was added 3N HCl and this mixture was extracted with ethylacetate and the organic extracts washed with water, dried, andconcentrated under reduced pressure. The residue was triturated withether/hexanes, the solvents decanted and the residue dried under reducedpressure to afford 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane asa tan liquid (41% yield). This procedure is further described in Y. Kim,Tetrahedron Lett. 30(21), 2833-2636 (1989).

Step D:—Synthesis of 2-Aza-2-benzyl-4-amino-3-oxobicyclo[3.2.1]octane

[1795] A solution of 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octanein 10 mL/mmole of ethanol and 5.8 mL/mmole of 3N HCl containing 0.5g/mmole of 10% Pd/C was saturated with hydrogen gas to 45 psi. Themixture was shaken for 3 hours and then filtered through a layer ofCelite. The filtrate was dried over sodium sulfate and concentratedunder reduced pressure to afford the title compound as a solid (86%yield). This procedure is further described in E. Reimann, Arch. Pharm.310, 102-109 (1977).

Example 5-1 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-γ-butyrolactam

[1796] Following General Procedure E above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-γ-butyrolactam (prepared by the procedure of S. Wilkinson, J.Chem. Soc. 1951, 104), the title compound was prepared as a solid havinga melting point of 217-222° C. The reaction was monitored by tlc onsilica gel (Rf=0.19 in 1:9 methanol/dichloromethane).

[1797] NMR data was as follows:

[1798]¹H-nmr (DMSO-d₆): δ=1.20 (m, 3H), 1.75 (m, 1H), 2.27 (m, 1H), 3.15(m, 2H), 3.51 (s, 1H), 3.52 (s, 1H), 4.28 (m, 2H), 6.99 (m, 2H), 7.09(m, 1H), 7.85 (m, 1H), 8.19 (m, 1H), 8.34 (d, J=7.8 Hz, 1H).

[1799]¹³C-nmr (DMSO-d₆): δ=18.7, 28.4, 28.5, 37.98, 38.00, 41.3, 41.5,48.07, 48.11, 49.4, 49.5, 101.9 (t, J=25.3 Hz), 112.2 (m), 140.8, 162.1(dd, J=13.5, 243.6 Hz), 168.6, 168.7, 172.27, 172.29, 174.2, 174.3.

[1800] C₁₅H₁₇N₃O₃F₂ (MW=325.32); mass spectroscopy (MH⁺) 326.

Example 5-2 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-δ-valerolactam

[1801] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-δ-valerolactam (prepared by the procedure of D. W. Adamson, J.Chem. Soc. 1943, 39), the title compound was prepared.

Example 5-3 Synthesis of1-Benzyl-3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-δ-valerolactam

[1802] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-benzyl-δ-valerolactam (Example 5-N), the title compoundwas prepared as a solid having a melting point of 172-175° C. Thereaction was monitored by tlc on silica gel (Rf=0.39 in 10%methanol/dichloromethane) and purification was by silica gelchromatography.

[1803] NMR data was as follows:

[1804]¹H-nmr (CDCl₃): δ=7.5 (m, 1H); 7.37 (d, J=7.7, 1H); 7.3 (m, 5H);6.80 (d, J=7.9, 2H); 6.65 (t, J=9.1, 8.9, 1H); 4.7 (m, 2H); 4.6 (m, 1H);4.3 (m, 1H); 3.50 (s, 2H); 3.2 (m, 2H); 1.9 (m, 4H); 1.3 (m, 3H).

[1805]¹³C-nmr (CDCl₃): δ=173.2, 170.3, 169.8, 165.2, 161.9, 139.4,137.1, 129.3, 128.4, 113.0, 112.8, 103.4, 102.0, 51.5, 51.3, 49.5, 47.1,43.2, 27.7, 21.5, 19.4.

[1806] C₂₃H₂₅F₂N₃O₃ (MW=429); mass spectroscopy (MH⁺) 430.

Example 5-4 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-4-methyl-ε-caprolactam

[1807] Following General Procedure B above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-4-methyl-ε-caprolactam (General Procedure—C), the title compoundwas prepared as a mixture of diasteromers. The reaction was monitored bytlc on silica gel (Rf=0.18 in 5% MeOH/dichloromethan).

[1808] NMR data was as follows:

[1809]¹H-nmr (DMSO-d₆; 2 diasteromers): δ=8.36 (m, 1H), 7.78 (m, 2H),7.06 (1H), 6.96 (m, 2H), 4.32 (m, 2H), 3.50 (s, 2H), 3.14 (m, 1H), 3.04(m, 1H), 1.80 (m, 1H), 1.70 (m, 1H), 1.08-1.55 (m, 3H), 1.20 (d, J=7.1Hz, 3H), 0.80 (m, 3H).

[1810]³C-nmr (DMSO-d₆; 2 diasteromers): δ=174.1, 174.0, 171.9, 171.8,169.1, 168.9, 162.4 (dd, J=13.6, 246.0 Hz), 140.9 (t, J=10.1 Hz), 112.4(dd, J=2.4, 24.2 Hz) 102.0, (t, J=26.0 Hz), 54.2, 54.0, 48.5(overlapping), 41.4, 36.7, 36.4, 34.5, 34.3, 28.2, 28.0, 18.9, 18.8,18.6, 18.0.

[1811] C₁₈H₂₃N₃O₃F₂ (MW=367.40); mass spectroscopy (M+Na) 390.5.

Example 5-5 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroquinolin-2-one

[1812] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1,2,3,4-tetrahydroquinolin-2-one (Example 5-A), the titlecompound was prepared as a mixture of diasteromers. The reaction wasmonitored by tlc on silica gel (Rf=0.38 in 25% ethyl acetate/hexanes)and purification was by flash chromatography using 25% ethylacetate/hexanes as the eluant.

[1813] NMR data was as follows:

[1814]¹H-nmr (DMSO-d₆; 2 diasteromers): δ=10.34 (d, 1H), 8.41 (d, 1H),8.23 (t, 1H), 7.20-6.86 (m, 7H), 4.40 (m, 2H), 3.52 (s, 2H), 3.52 (s,2H), 3.05-2.79 (m, 2H), 1.29 (d, 1.5H), 1.24 (d, 1.5H).

[1815]¹³C-nmr (DMSO-d₆; 2 diasteromers): δ=172.66, 169.31, 169.21,169.13, 168.89, 137.85, 128.58, 126.46, 127.94, 122.88, 122.79, 122.69,122.64, 115.48, 112.97, 112.88, 112.73. 112.59, 112.51, 102.24, 48.61,48.17, 41.68, 31.72, 18.96, 18.87.

[1816] C₂₀H₁₉N₃O₃F₂ (MW=387.39).

Example 5-6 Synthesis of1-Benzyl-3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroquinolin-2-one

[1817] Following General Procedure C above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1-benzyl-1,2,3,4-tetrahydroquinolin-2-one (General Procedure5-A), the title compound was prepared as a solid having a melting pointof 196-199° C. The reaction was monitored by tlc on silica gel (Rf=0.35in 5% methanol/dichloromethane) and purification was by flashchromatography using 5% methanol/dichloromethane as the eluant.

[1818] NMR data was as follows:

[1819]¹H-nmr (CDCl₃): δ=7.4-6.8 (m, 12H), 6.7 (m, 1H), 6.45 (d, 1H), 5.4(d, 1H), 4.9 (d, 1H), 4.6 (m, 2H), 3.55 (s, 2H), 3.45-3.40 (2×d, 1H),2.85 (t, 1H), 1.45 (t, 3H).

[1820]¹³C-nmr (CDCl₃): δ=172.7, 172.6, 169.9, 169.7, 169.2, 169.2,165.4, 165.2, 162.1, 161.9, 139.3, 138.7, 138.6, 136.8, 129.4, 129.3,128.7, 128.0, 126.9, 124.8, 124.8, 124.6, 124.5, 116.5, 113.1, 113.05,113.0, 112.9, 112.86, 112.8, 112.8, 112.7, 103.8, 103.5, 103.1, 50.1,49.7, 49.6, 48.0, 47.9, 43.5, 32.3, 32.12, 32.1, 19.4, 19.2.

[1821] C₂₇H₂₅N₃O₃F₂ (MW=477.51); mass spectroscopy (MH⁺) 478.

Example 5-7 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroisoquinolin-3-one

[1822] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine and4-amino-1,2,3,4-tetrahydroisoquinoline-3-one, the title compound wasprepared as a solid having a melting point of 243-244° C.

[1823] NMR data was as follows:

[1824]¹H-nmr (DMSO-d₆): δ=8.46 (bt, J=8.25 Hz, 2H), 8.36-8.38 (bd, J=4Hz, 1H), 7.3-7.0 (m, 7H), 5.34-5.39 (bd, J=10 Hz, 1H), 4.5-4.4 (m, 2H),4.2-4.23 (m, 1H), 3.56 (s, 2H), 1.33 (d, J=7 Hz, 3H).

[1825] C₂₀H₁₉N₃O₃F₂ (MW=387.1); mass spectroscopy: 387.

Example 5-8 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1826] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-2-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure5-D), the title compound was prepared as a solid having a melting pointof 144-145° C.

[1827] NMR data was as follows:

[1828]¹H-nmr (DMSO-d₆): δ=7.8 (bd, 0.5H), 7.57 (bd, 0.5H), 7.26-7.0 (m,9H), 6.8-6.6 (m, 2H), 6.66-6.3 (m, 1H), 5.5-5.43 (m, 1H), 4.79-4.45 (m,5H), 4.10 (t, J=14 Hz, 1H), 3.49 (s, 2H), 5.52 (d, J=7.0 Hz, 1.5H), 1.49(d, J=7.0 Hz, 1.5H).

[1829] C₂₇H₂₅N₃O₃F₂ (MW=477); mass spectroscopy: 477.

Example 5-9 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1830] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-1-methyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure5-D), the title compound was prepared as a solid having a melting pointof 205-206° C.

[1831] NMR data was as follows:

[1832]¹H-nmr (DMSO-d₆): δ=8.6-8.24 (m, 3H), 7.3-7.0 (m, 7H aromatic),5.4-5.39 (m, 1H), 4.58-4.4 (m, 2H), 3.54 (s, 2H), 1.49-1.38 (m, 1H),1.35-1.3 (m, 6H).

[1833] C₂₁H₂₁N₃O₃F₂ (MW=401); mass spectroscopy: 401.

Example 5-10 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1834] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure5-D), the title compound was prepared as a solid having a melting pointof 200-205° C.

[1835] NMR data was as follows:

[1836]¹H-nmr (DMSO-d₆): δ=9.06 (bt, J=2 Hz, 1H), 8.69-8.43 (m, 2Hz),7.55-7.0 (m, 2H), 6.1 (bd, J=8 Hz, 0.25H), 5,7-5.5 (m, 1H), 5.5 (bd, J=8Hz, 0.25H), 5.2-5.19 (bd, J=8 Hz, 0.5H), 4.48-4.4 (m, 1H), 3.57-3.5 (m,2H), 315 (s, 1H), 1.4-1.2 (m, 3H).

[1837] C₂₆H₂₃N₃O₃F₂ (MW=463); mass spectroscopy: 463.2.

[1838] By employing the above procedure usingtrans-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one andpurifying the resulting product by LC 2000 chromatography, eluting withdichloromethane/methanol (97:3), the following isomers oftrans-4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-onewere prepared:

[1839] Isomer 1: m.p.=249-250° C.

[1840] Isomer 2: m.p.=232-233° C.

[1841] By employing the above procedure usingcis-4-amino-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one and purifyingthe resulting product by LC 2000 chromatography, eluting withdichloromethane/methanol (97:3), the following isomers ofcis4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-onewere prepared:

[1842] Isomer 1: m.p.=244.1-244.5° C.

[1843] Isomer 2: m.p.=247-248° C.

Example 5-11 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-6fluoro-1,2,3,4-tetrahydroisoquinolin-3-one

[1844] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-6-fluoro-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure5-D), the title compound was prepared as a solid having a melting pointof 195-200° C.

[1845] NMR data was as follows:

[1846]¹H-nmr (DMSO-d₆): δ=8.6-8.41 (m, 3H), 7.4-7.24 (m, 1H), 7.09-6.98(m, 4H), 6.8-6.77 (bd, J=9 Hz, 1H), 5.43-5.30 (m, 1H), 4.46-4.42 (m,2H), 4.23-4.19 (m, 1H), 3.34 (s, 2H), 1.37-1.31 (m, 3H).

[1847] C₁₉H₁₈N₃O₃F₂ (MW=405.3); mass spectroscopy: 405.

Example 5-12 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-7-fluoro-1,2,3,4-tetrahydroisoquinolin-3-one

[1848] Following General Procedure D above usingN-(3,5-difluorophenyl)acetyl-L-alanine (Example B) and4-amino-7-fluoro-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-E), thetitle compound was prepared. The product was purified by slurrying inether/hexanes (1:1) and by LC 2000 chromatography, eluting withmethanol/ethyl acetate (1:99), to give the product as a solid (Isomer 1:m.p.=230-235° C.; Isomer 2: m.p.=195-200° C.).

[1849] NMR data was as follows:

[1850]¹H-nmr (DMSO-d₆): δ=7.25-6.9 (m, 6H), 5.4 (d, J=8 Hz, 1H), 4.6-4.4(m, 2H), 3.55 (s, 2H), 1.35 (d, J=7.5 Hz, 1.5H), 1.32 (d, J=7.2 Hz,1.5H).

[1851] C₂₀H₁₈N₃O₃F₃ (MW=405); mass spectroscopy: 405.

Example 5-13 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1852] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinoline-3-one (GeneralProcedure 5-D), the title compound was prepared as a solid having amelting point of 75-76° C.

[1853] C₂₈H₂₇N₃O₃F₂ (MW=491); mass spectroscopy: 491.2.

Example 5-14 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1854] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure5-D), the title compound was prepared as a solid having a melting pointof 174-175° C.

[1855] NMR data was as follows:

[1856]¹H-nmr (DMSO-d₆): δ=8.57-8.47 (m, 1H), 8.45 (d, J=7.6 Hz, 1H),7.26-7.06 (m, 7H aromatic), 5.38 (d, J=8.3 Hz, 1H), 4.68 (d, J=16 Hz,1H), 4.41 (pentet, J=8 Hz, 1H), 4.42 (d, J=16 Hz, 1H), 3.5 (s, 2H), 2.9(s, 3H), 1.34 (d, J=8 Hz, 1.5 Hz), 1.32 (d, J=8 Hz, 1.5H).

[1857] C₂₁H₂₁N₃O₃F₂ (MW=401); mass spectroscopy: 401.

Example 5-15 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-6phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1858] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-6-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure5-D), the title compound was prepared. The product was purified by LC2000 chromatography, eluting with ethyl acetate.

[1859] NMR data was as follows:

[1860]¹H-nmr (CD₃OD/CDCl₃): δ=8.8 (bd, 0.5H), 7.74 (bd, 0.5H), 7.4-7.16(m, 6H), 6.69 (bs, 1H), 6.69 (bs, 1H), 6.5 (m, 1H), 5.39 (bs, 1H),4.45-3.95 (m, 4H), 1.37-1.33 (m, 3H).

[1861] C₂₆H₂₃N₃O₃F₂ (MW=463.49); mass spectroscopy: 463.4.

Example 5-16 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-7-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1862] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-7-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-H), thetitle compound was prepared as a solid having a melting point>240° C.(dec.).

[1863] NMR data was as follows:

[1864]¹H-nmr (CDCl₃): δ=7.5-7.18 (m, 10H), 6.85-6.74 (m, 4H), 4.9-4.57(m, 1H), 4.56-4.37 (m, 2H), 3.58 (s, 1H), 3.55 (s, 1H), 1.53 (d, J=6 Hz,1.5H), 1.47 (d, J=6 Hz, 1.5H).

[1865] C₂₆H₂₃N₃O₃F₂ (MW=463); mass spectroscopy: 463.

Example 5-17 Synthesis of(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-(9-aminofluroren-1-yl)glycineδ-Lactam

[1866] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and(9-aminofluroren-1-yl)glycine δ-lactam (General Procedure 5-D), thetitle compound was prepared as a solid having a melting point>240° C.(dec.).

[1867] NMR data was as follows:

[1868]¹H-nmr (DMSO-d₆): δ=8.0-6.8 (bm, 10H), 6.3-5.75 (bs, 1H), 5.75-5.4(bs, 1H), 4.1-4.5 (bs, 1H), 3.7-3.35 (bm, 2H), 3.3 (s, 2H), 1.4-1.0 (bm,3H)

[1869] C₂₆H₂₁N₃O₃F₂ (MW=461); mass spectroscopy: 461.

Example 5-18 Synthesis of3-(N′-(Phenylacetyl)-L-alaninyl)amino-ε-caprolactam

[1870] Following General Procedure B above usingN-(phenylacetyl)-L-alanine (Example A) and 3-amino-ε-caprolactam(Sigma), the title compound was prepared as a solid having a meltingpoint of 200-202° C. The reaction was monitored by tlc on silica gel(Rf=0.30 in 1:9 methanol/dichloromethane).

[1871] NMR data was as follows:

[1872]¹H-nmr (DMSO-d₆): δ=8.35 (m, 1H), 7.85 (m, 2H), 7.28-7.32 (m, 5H),4.2-24.40 (m, 2H), 3.46 (s, 2H), 2.98-3.13 (m, 2H), 1.53-1.90 (m, 4H),1.26-1.40 (m, 1H), 1.20 (m, 4H).

[1873]¹³C-nmr (DMSO-d₆) δ=174.05, 174.02, 171.2, 171.1, 169.9, 169.8,136.31, 131.29, 129.1, 129.0, 128.2, 126.3, 51.3, 48.3, 42.0, 40.6,31.2, 31.0, 28.8, 27.6, 18.2, 18.1.

[1874] C₁₇H₂₃N₃O₃ (MW=317.39); mass spectroscopy (MH⁺) 316.

Example 5-19 Synthesis of3-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)-amino-ε-caprolactam

[1875] Following General Procedure B above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-ε-caprolactam (Aldrich), the title compound was prepared asa solid having a melting point>225C. The reaction was monitored by tlcon silica gel (Rf=0.36 in 1:9 methanol/dichloromethane).

[1876] NMR data was as follows:

[1877]¹H-nmr (DMSO-d₆): δ=1.10-1.40 (m, 2H), 1.21 (d, J=7.1 Hz, 3H),1.55-1.90 (m, 4H), 3.05 (m, 1H), 3.17 (m, 1H), 3.52 (s, 2H), 4.29 (m,2H), 6.98 (m, 2H), 7.08 (m, 1H), 7.84 (m, 2H), 8.43 (d, J=7.3 Hz, 1H).

[1878]¹³C-nmr (DMSO-d₆) δ=18.0, 27.6, 28.8, 31.0, 40.6, 41.3, 48 .4,51.3, 101.9 (t, J=25.6 Hz), 112.3 (dd, J=7.5, 16.8 Hz), 140.6, 162.1(dd, J=13.2, 243.9 Hz), 168.8, 171.1, 174.0.

[1879] C₁₇H₂₁N₃O₃F₂ (MW=353.37 ); mass spectroscopy (MH⁺) 354.

Example 5-20 Synthesis of3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-ε-caprolactam

[1880] Following General Procedure B above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-benzyl-ε-caprolactam (prepared from3-(S)-amino-ε-caprolactam and benzyl bromide using the procedure ofExample 6-A and General Procedure 6-B), the title compound was preparedas a solid having a melting point of 176-178° C. The reaction wasmonitored by tlc on silica gel (Rf=0.44 in 10% methanol/dichloromethane)and purification was by precipitation from water.

[1881] NMR data was as follows:

[1882]¹H-nmr (CDCl₃): δ=1.20 (m, 1H), 1.39 (d, J=7.0 Hz, 3H), 1.50 (m,1H), 1.65-2.06 (m, 4H), 3.24 (m, 1H), 3.45 (m, 1H), 3.54 (s, 2H), 4.51(m, 2H), 4.60 (m, 1H), 4.72 (d, 14.5 Hz, 1H), 6.48.(d, J=7.1 Hz, 1H),6.72 (m, 1H), 6.83 (m, 2H), 7.20-7.41 (m, 6H).

[1883]¹³C-nmr (CDCl₃): δ=19.0, 26.9, 27.5, 31.7, 42.8, 48.0, 49.0, 51.5,52.4, 102.6 (t, J=25.2 Hz), 112.2 (dd, J=8.0, 17.0 Hz), 127.6, 128.1,128.7, 136.7, 138.4, 162.9 (dd, J=12.8, 247.3 Hz), 169.0, 171.0, 172.5.

[1884] C₂₄H₂₇N₃O₃F₂ (MW=443.50); mass spectroscopy (MH⁺) 444.

Example 5-21 Synthesis of3-(S)-N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(2-Methoxyethyl)-ε-caprolactam

[1885] Following General Procedure B above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-(2-methoxyethyl)-ε-caprolactam (prepared from3-(S)-amino-ε-caprolactam and 2-methoxyethyl bromide using the procedureof Example 6-A and General Procedure 6-B), the title compound wasprepared as a solid having a melting point of 102-106° C. The reactionwas monitored by tlc on silica gel (Rf=0.08 in 5%methanol/dichloromethane).

[1886] NMR data was as follows:

[1887]¹H-nmr (CDCl₃): δ=1.38 (d, J=7.1 Hz, 3H), 1.48 (m, 2H), 1.82 (m,2H), 1.96 (m, 2H), 3.35 (s, 3H), 3.38 (m, 1H), 3.47-3.70 (m, 7H), 4.55(m, 2H), 6.75 (m, 2H), 6.85 (m, 2H), 7.42 (d, J=6.0 Hz, 1H).

[1888]¹³C-nmr (CDCl₃): δ=19.0, 27.1, 27.6, 31.7, 42.8, 48.7, 49.0, 49.9,52.4, 58.8, 70.9, 102.6 (t, J=25.2 Hz), 112.2 (dd, J=7.8, 16.9 Hz),138.4, (164.5, 161.4, 161.2 as multiplet), 169.0, 171.0, 172.4.

[1889] C₂₀H₂₇N₃O₄F₂ (MW=411.45); mass spectroscopy (MH⁺) 412.

Example 5-22 Synthesis of3-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-ε-caprolactam

[1890] Following General Procedure B above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-ethyl-ε-caprolactam (prepared from3-(S)-amino-ε-caprolactam and ethyl iodide using the procedure ofExample 6-A and General Procedure 6-B), the title compound was preparedas a solid having a melting point of 162-165° C. The reaction wasmonitored by tlc on silica gel (Rf=0.43 in 10%methanol/dichloromethane).

[1891] NMR data was as follows:

[1892]¹H-nmr (CDCl₃): δ=1.12 (t, J=7.1 Hz, 3H), 1.40 (m, 2H), 1.36 (d,J=7.0 Hz, 3H), 1.70-2.00 (m, 4H), 3.24 (m, 1H), 3.50 (m, 3H), 3.53 (s,2H), 4.50 (m, 2H), 6.70 (m, 2H), 6.83 (m, 2H), 7.39 (d, J=6.0 Hz, 1H).

[1893]¹³C-nmr (CDCl₃): δ=13.1, 19.1, 27.6, 27.7, 31.7, 42.8, 43.5, 48.1,49.0, 52.3, 102.6 (t, J=25.1 Hz), 112.2 (dd, J=7.9, 17.0 Hz), 138.3,138.4, 163.0 (dd, J=12.8, 247.1 Hz), 168.9, 170.9, 171.8.

[1894] C₁₉H₂₅N₃O₃F₂ (MW=381.43); mass spectroscopy (MH⁺) 382.

Example 5-23 Synthesis of3-N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-ε-caprolactam

[1895] Following General Procedure B above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-5-ethyl-ε-caprolactam (General Procedure 5-C), the titlecompound was prepared as a solid. The reaction was monitored by tic onsilica gel (Rf=0.13 in 5% methanol/dichloromethane).

[1896] NMR data was as follows:

[1897]¹H-nmr (CDCl₃): δ=0.98 (t, J=7.4 Hz, 3H), 1.31 (d, J=7.0 Hz,1.5H), 1.35 (d, J=7.1 Hz, 1.5H), 1.55 (m, 1H), 1.65 (m, 3H), 1.82 (m,2H), 1.95 (m, 1H), 3.06 (m, 1H), 3.41 (m, 1H), 3.49 (s, 1H), 3.52 (s,1H), 4.55-4.72 (m, 2H), 6.38 (m, 0.5H), 6.63-6.90 (m, 4.5H), 7.37 (d,J=6.0 Hz, 0.5H), 7.52 (d, J=6.2 Hz, 0.5H).

[1898]¹³C-nmr (CDCl₃): δ=12.07, 12.11, 19.0, 19.2, 24.4, 24.5, 31.9,32.0, 35.0, 35.3, 35.7, 36.9, 37.0, 42.8, 47.4, 47.6, 48.8, 48.9, 102.7(t),.102.6 (t), 122.2 (multiplet of 8), 138.35, 138.41, 138.5, 163.0(dd, J=12.8, 247.1 Hz), 168.9, 169.2, 171.1, 171.3, 174.8, 174.9.

[1899] C₁₉H₂₅N₃O₃F₂ (MW=381.43); mass spectroscopy (MH⁺) 382.

Example 5-24 Synthesis of3-N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-ε-caprolactam

[1900] Following General Procedure B above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-5-ethyl-ε-caprolactam (General Procedure 5-C), the titlecompound was prepared as a solid having a melting point of 201-204° C.(decom.). The reaction was monitored by tlc on silica gel (Rf=0.04 in 5%methanol/dichloromethane).

[1901] NMR data was as follows:

[1902]¹H-nmr (CD₃OD): δ=0.70 (t, J=7.1 Hz, 3H), 0.78-1.20 (m, 7H), 1.49(m, 1H), 1.68 (m, 2H), 3.07 (m, 2H), 3.38 (s, 2H), 4.19 (m, 1H), 4.31(d, J=11.0 Hz, 1H), 6.61 (m, 1H), 6.72 (m, 2H).

[1903]¹³C-nmr (CD₃OD): δ=11.47, 11.49, 17.8, 17.9, 31.0, 35.97, 36.03,38.2, 38.3, 41.6, 42.7 (multiplet of 7), 50.7, 50.8, 52.3, 103.0 (2triplets of 6), 113.2 (2 dd of 8), 140.9, 141.0, 164.3 (dd, J=15.5,258.3 Hz), 172.5 (overlapping of 2), 173.7, 173.9, 176.5, 176.6.

[1904] C₁₉H₂₅N₃O₃F₂ (MW=381.43); mass spectroscopy (MH⁺) 382.

Example 5-25 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl-amino)-7-benzyl-ε-caprolactam

[1905] Following General Procedure B above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-7-benzyl-ε-caprolactam (General Procedure 5-C), the titlecompound was prepared as an oil. The reaction was monitored by tlc onsilica gel (Rf=0.04 in 5% methanol/dichloromethane).

[1906] NMR data was as follows:

[1907]¹H-nmr (CDCl₃): δ=1.35 (m, 3H), 1.45 (m, 1H), 1.80 (m, 2H), 2.05(d, J=7.2 Hz, 2H), 2.10 (m, 1H), 2.97 (m, 2H), 3.51 and 3.52 (2 s, 3H),4.60 (m, 2H), 6.50-6.85 (m, 5H), 7.15 (m, 2H), 7.26 (m, 3H), 7.45 (m,1H).

[1908]¹³C-nmr (CDCl₃): δ=18.7, 20.0, 21.6, 30.2, 30.4, 30.7, 39.1, 39.3,42.5, 48.70, 48.74, 53.02, 53.06, 53.89, 53.97, 102.5 (, J=25.4 Hz),112.2 (dd, J=8.3, 17.2 Hz), 126.68, 126.74, 128.67, 128.71, 128.9,138.0, 138.1, 138.6, 138.7, 138.8, 163.0 (dd, J=13.0, 249.0 Hz), 169.5,169.6, 172.0, 174.4, 175.0.

[1909] C₂₄H₂₇N₃O₃F₂ (MW=443.50).

Example 5-26 Synthesis of3-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-benzy1-4,7-methano-ε-caprolactam

[1910] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-benzyl-4,7-methano-ε-caprolactam (i.e.,4-amino-2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane hydrochloride fromExample 5-O), the title compound was prepared as an oil. The reactionwas monitored by tlc on silica gel (Rf=0.42 in 10%methanol/dichloromethane) and purification was by silica gelchromatography.

[1911] NMR data was as follows:

[1912]¹H-nmr (CDCl₃): δ=7.3 (m, 5H); 6.82 (t, J=6.3, 6.0, 2H); 6.6 (m,1H); 5.14 (dd, J=6.5, 8.5, 6.4, 1H); 4.6 (m, 2H); 3.79( dd, J=10.3, 4.5,10.4, 1H). 3.56 (s, 1H); 3.51 (s, 2H); 2.8 (m, 1H); 2.57 (s, 1HO; 1.96(d, J=12.1, 1H); 1.7 (m, 4H); 1.34 (d, J=7.0, 3H).

[1913]¹³C-nmr (CDCl₃): δ=173.4, 170.3, 168.9, 165.2, 139.4, 137.3,129.3, 128.5, 128.2, 112.9, 112.8, 112.7, 112.6, 103.4, 103.0, 102.7,59.0, 49.6, 43.1, 38.1, 37.8, 36.6, 32.6, 22.7, 19.2.

[1914] C₂₅H₂₇F₂N₃O₃ (MW=455); mass spectroscopy (MH⁺) 456.

Example 5-27 Synthesis of3-(S)-(N′-(Cyclopentylacetyl)-L-alaninyl)amino-1-benzyl-ε-caprolactam

[1915] Following General Procedure A above usingN-(cyclopentylacetyl)-L-alanine (Example D) and(S)-3-amino-1-benzyl-ε-caprolactam (prepared from3-(S)-amino-ε-caprolactam and benzyl bromide using the procedure ofExample 6-A and General Procedure 6-B), the title compound was prepared.The reaction was monitored by tlc on silica gel (Rf=0.37 in 5%methanol/dichloromethane) and purification was by preparative thin layerchromatography using 5% methanol/dichloromethane as the eluant.

[1916] NMR data was as follows:

[1917]¹H-nmr (CDCl₃): δ=7.42 (d, J=6.0 Hz, 1H), 7.15-7.05 (m, 5H), 6.36(d, 7.2 Hz, 1H), 4.8-4.4 (m, 4H), 3.5-3.3 (m, 1H), 3.3-3.1 (m, 1H),2.3-1.0 (m 20H).

[1918]³C-nmr (CDCl₃): δ=172.8, 172.4, 171.5, 136.9, 128.7, 128.2, 127.7,52.3, 51.4, 48.6, 47.9, 47.6, 42.6, 36.9, 32.34, 32.28, 31.6, 27.5,26.8, 24.8, 19.0, 18.4.

[1919] C₂₃H₃₃N₃O₃ (MW=399.54); mass spectroscopy (M+Na) 422.

Example 5-28 Synthesis of3-(S)-(N′-(Cyclopentylacetyl)-L-phenylglycinyl)amino-1-benzyl-ε-caprolactam

[1920] Following General Procedure A aboveN-(cyclopentylacetyl)-L-2-phenylglycine (Example C) and3-(S)-amino-1-benzyl-ε-caprolactam (prepared from3-(S)-amino-ε-caprolactam and benzyl bromide using the procedure ofExample 6-A and General Procedure 6-B), the title compound was prepared.The reaction was monitored by tlc on silica gel (Rf=0.40 in 5%methanol/dichloromethane) and purification was by preparative thin layerchromatography using 5% methanol/dichloromethane as the eluant.

[1921] NMR data was as follows:

[1922]¹H-nmr (CDCl₃): δ=7.4-7.15 (m, 11H), 6.79 (d, J=6.6 Hz, 1H), 5.48(d, J=7.2 Hz, 1H), 4.5 (m, 3H), 3.4-3.1 (m, 2H), 2.3-1.0 (m, 17H).

[1923]¹³C-nmr (CDCl₃): δ=172.3, 172.1, 168.9, 138.0, 129.0, 128.6,128.2, 128.1, 127.6, 127.0, 57.1, 52.6, 51.3, 47.8, 42.5, 36.8, 32.33,32.27, 31.4, 27.4, 26.8, 24.7.

[1924] C₂₃H₃₃N₃O₃ (MW=461.61); mass spectroscopy (M+Na) 484.

Example 5-29 Synthesis of3-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(2-phenethyl)-ε-caprolactam

[1925] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-(2-phenethyl)-ε-caprolactam (prepared from3-(S)-amino-ε-caprolactam and 2-phenethyl bromide using the procedure ofExample 6-A and General Procedure 6-B), the title compound was prepared.The reaction was monitored by tlc on silica gel (Rf=0.36 in 5%methanol/dichloromethane) and purification was by preparative thin layerchromatography using 5% methanol/dichloromethane as the eluant.

[1926] NMR data was as follows:

[1927]¹H-nmr (CDCl₃): δ=7.60 (d, J=6.3 Hz, 1H), 7.3-7.1 (m, 6H), 6.81(m, 2H), 6.66 (m, 1H), 4.6 (m, 2H), 3.75 (m, 1H), 3.51 (s, 2H), 3.5-3.4(m, 2H), 3.05 (m, 1H), 2.8 (m, 2H), 1.95-1.6 (m, 4H), 1.5-1.1 (m(includes d at 1.36, J=7.2 Hz, 3H), 5H).

[1928]¹³C-nmr (CDCl₃): δ=172.3, 171.5, 169.2, 164.6, 164.5, 161.4,161.2, 139.0, 138.8, 138.7, 138.6, 128.6, 128.5, 126.4, 112.3, 112.2,112.05, 111.95, 102.7, 102.3, 102.0, 52.2, 50.8, 49.2, 48.9, 42.4, 34.1,31.5, 27.3, 27.1, 18.8.

[1929] C₂₅H₂₉F₂N₃O₃ (MW=457.52); mass spectroscopy (M+Na) 480.

Example 5-30 Synthesis of3-(S)-(N′-(Cyclopentylacetyl)-L-phenylglycinyl)amino-1-(2-phenethyl)-ε-caprolactam

[1930] Following General Procedure A above usingN-(cyclopentylacetyl)-L-phenylglycine (Example C) and3-(S)-amino-1-(2-phenethyl)-ε-caprolactam (prepared from3-(S)-amino-ε-caprolactam and 2-phenethyl bromide using the procedure ofExample 6-A and General Procedure 6-B), the title compound was prepared.The reaction was monitored by tlc on silica gel (Rf=0.47 in 5%methanol/dichloromethane) and purification was by preparative thin layerchromatography using 5% methanol/dichloromethane as the eluant.

[1931] NMR data was as follows:

[1932]¹H-nmr (CDCl₃): δ=7.4-7.1 (m, 11H), 6.88 (d, J=7.2 Hz, 1H), 5.49(d, J=7.2 Hz, 1H), 4.2 (m, 1H), 3.7-3.6 (m, 1H), 3.5-3.3 (m, 2H),3.1-3.0 (m, 1H), 2.9-2.7 (m, 2H), 2.3-1.0 (m, 17H).

[1933]¹³C-nmr (CDCl₃): δ=172.2, 171.0, 169.0, 138.6, 138.2, 129.0,128.7, 128.6, 128.2, 127.0, 126.5, 57.0, 52.6, 50.8, 49.3, 44.4, 42.5,36.9, 34.2, 32.4, 32.3, 31.4, 27.5, 27.2, 24.8.

[1934] C₂₉H₃₇N₃O₃ (MW=475.64); mass spectroscopy (M+Na) 498.

Example 5-31 Synthesis of3-(N′-(3,4-Dichlorophenyl)-D,L-alaninyl)amino-ε-caprolactam

[1935] Following General Procedure A above usingN-(3,4-dichlorophenyl)-D,L-alanine (Example Q) and3-(S)-amino-ε-caprolactam (Sigma), the title compound was prepared as asolid having a melting point of 199° C. The reaction was monitored bytlc on silica gel (Rf=0.4 in 50% ethyl acetate/hexanes) and purificationwas by preparative thin layer chromatography using 50% ethylacetate/hexanes as the eluant.

[1936] NMR data was as follows:

[1937]¹H-nmr (DMSO-d₆): δ=7.2(d, 1H); 6.7 (d, 1H,); 6.4 (dd, 1H); 4.30(bs, 1H); 4.1 (m, 2H); 2.9 (m, 2H); 1.7 (m, 6H); 1.3 (t, 3H).

[1938]¹³C-nmr (DMSO-d₆) δ=175; 171; 146.7; 133; 131; 121; 114.9; 112.6;52.4; 28.3; 27.5; 19.5; 18.2; 18.1.

[1939] C₁₅H₁₉N₃O₂Cl₂ (MW=344.24); mass spectroscopy (MH⁺) 345.

Example 5-32 Synthesis of3-(S)-(N′-(cyclopropylacetyl)-L-phenylglycinyl)amino-1-methyl-ε-caprolactam

[1940] Following General Procedure A above usingN-(eyclopropylacetyl)-L-phenylglycine (Example F) and3-(S)-amino-1-methyl-ε-caprolactam (prepared from3-(S)-amino-ε-caprolactam and methyl iodide using the procedure ofExample 6-A and General Procedure 6-B), the title compound was preparedas a solid having a melting point>200° C. The reaction was monitored bytlc on silica gel (Rf=0.41 in 10% methanol/dichloromethane) andpurification was by recrystallization from ethyl acetate and hexanes.

[1941] NMR data was as follows:

[1942]¹H-nmr (CDCl₃): δ=7.5-7.2 (m, 7H), 5.49 (d, J=6.6 Hz, 1H), 4.46(m, 1H), 3.50 (m, 1H), 3.10 (m, 1H), 2.97 (s, 3H), 2.1-1.7 (m, 4H),1.5-1.3 (m, 2H), 1.0 (m, 1H), 0.6 (m, 2H), 0.2 (m, 2H).

[1943]¹³C-nmr (CDCl₃): δ=172.1, 171.8, 168.9, 138.1, 129.0, 128.3,127.0, 57.0, 52.4, 50.2, 41.1, 35.8, 31.3, 27.5, 26.4, 6.8, 4.4.

[1944] C₂₀H₂₇N₃O₃ (MW=357.46).

Example 5-33 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-8-octanelactam

[1945] Following General Procedure B above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-8-octanelactam (i.e., 2-oxo-1-azacyclononane prepared asdescribed in General Procedure 5-C), the title compound was prepared asa solid having a melting point of >220° C.

[1946] NMR data was as follows:

[1947]¹H-nmr (DMSO-d₆): δ=1.00-1.85 (m, 12H), 2.73 (m, 1H), 3.33 (br s,2H), 3.49 (br s, 2H), 4.07 (m, 1H), 4.28 (m, 1H), 6.95 (m, 2H), 7.06 (m,1H), 7.75-7.90 (m, 2H), 8.30 (d, J=7.2 Hz, 1H).

[1948]¹³C-nmr (DMSO-d₆): δ=18.2, 18.6, 21.1, 23.5, 27.9, 28.1, 32.3,32.6, 41.3, 48.0, 48.1, 52.9, 53.0, 102.0 (t, J=25.9 Hz), 112.4 (d,J=24.1 Hz), 141.0 (t, J=11.2 Hz), 162.3 )dd, J=13.5, 244.5 Hz), 168.9,171.9, 173.1, 173.2.

[1949] C₁₉H₂₅N₃O₃F₂ (MW=381.43); mass spectroscopy (M-H) 380.

Example 5-34 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1950] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure5-D), the title compound was prepared as a solid having a melting pointof 159-166° C.

[1951] C₂₇H₂₅N₃O₃F₂ (MW=477); mass spectroscopy: 477.

Example 5-35 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1952] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-1-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-I), thetitle compound was prepared as a solid having a melting point of106-107° C.

[1953] C₂₇H₂₅N₃O₃F₂ (MW=477.52); mass spectroscopy: 478.

Example 5-36 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one

[1954] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (GeneralProcedure 5-D), the title compound was prepared as a solid having amelting point of 115° C.

[1955] C₂₇H₂₄N₃O₃F₂ (MW=476); mass spectroscopy: 477.

Example 5-37 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

[1956] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-one (Example5-C), the title compound was prepared as a solid having a melting pointof 100° C.

[1957] C₂₅H₂₂N₄O₃F₂ (MW=464); mass spectroscopy: 464.1.

Example 5-38 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

[1958] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinoline-3-one (Example5-D), the title compound was prepared as a solid having a melting pointof 100-120° C.

[1959] C₂₅H₂₂N₄O₃F₂ (MW=464); mass spectroscopy: 464.

Example 5-39 Synthesis of4-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-one

[1960] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and4-amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-one (Example5-B), the title compound was prepared as a solid having a melting pointof 100° C.

[1961] C₂₅H₂₂N₄O₃F₂ (MW=464); mass spectroscopy: 464.

Example 5-40 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-1-methyl-2-indolinone

[1962] Following General Procedure I above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1-methyl-2-indolinone monohydrochloride (Example 5-J), the titlecompound, as a ˜1:1 diastereomeric mixture at C3 of the indolinone, wasprepared as a white solid having a decomposition point of 215-220° C.Purification was by flash chromatography eluting with 3:1 CH₂Cl₂/EtOAcgradient to straight EtOAc followed by recrystalization from CHCl₃.R_(f)=0.16 and 0.22 (EtOAc).

[1963] C₂₀H₁₉F₂N₃O₃ (MW 387.39); mass spectroscopy (MH+) 387.0.

[1964] Anal. Calcd for C₂₀H₁₉F₂N₃O₃: C, 62.01; H, 4.94; N, 10.85. Found:C, 61.76; H, 5.17; N, 10.65.

Example 5-41 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril

[1965] Following General Procedure I above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and the tin complexof 3-amino-1-methyl-4-phenyl-3,4-trans-dihydrocarbostyril (Example 5-K),the title compound, as a ˜1:1.8 diastereomeric mixture of the two3,4-trans-dihydrocarbostyril isomers, was prepared as a white solid(melting point=118-128° C.). Purification was by flash chromatographyeluting with straight EtOAc. R_(f)=0.37 (EtOAc).

[1966] C₂₇H₂₅F₂N₃O₃ (MW 477.52); mass spectroscopy (MH+) 477.

[1967] Anal. Calcd for C₂₇H₂₅F₂N₃O₃: C, 67.91; H, 5.28; N, 8.80. Found:C, 67.78; H, 5.35; N, 8.55.

Example 5-42 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-1-methyl-4phenyl-3,4cis-dihydrocarbostyril

[1968] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1-methyl4-phenyl-3,4-cis-dihydrocarbostyril (Example 5-L), thetitle compound was prepared as a white solid (m.p. 152-153° C.).

[1969] C₂₇H₂₅F₂N₃O₃ (MW 477.52); mass spectroscopy (MH+) 478.2, (MH−)476.2.

[1970] Anal. Calcd for C₂₇H₂₅F₂N₃O₃: C, 67.91; H, 5.28; N, 8.80. Found:C, 67.61; H, 5.41; N, 8.78.

Example 5-43 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-4phenyl-3,4-trans-dihydrocarbostyril

[1971] Step A: Following General Procedure I above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and the tin complexof 3-amino-1-tert-butoxycarbonyl-4-phenyl-3,4-trans-dihydrocarbostyril(Example 5-M),3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-1-tert-butoxycarbonyl4-phenyl-3,4-trans-dihydrocarbostyrilwas prepared.

[1972] Step B: The title compound was prepared following GeneralProcedure 5-B using the product from Step A, as a ˜1:1.4 diastereomericmixture of the two 3,4-trans-dihydrocarbostyril isomers. The product waspurified by flash chromatography eluting with CH₂Cl₂/MeOH (98:2 gradientto 94:6) and a second flash chromatography eluting with straight EtOActo yield a white solid (melting point=137-147° C.). R_(f)=0.42 (EtOAc).

[1973] C₂₆H₂₃F₂N₃O₃ (MW 463.49); mass spectroscopy (M+) 463.1

[1974] Anal. Calcd for C₂₆H₂₃F₂N₃O₃: C, 67.38; H, 5.00; N, 9.07. Found:C, 67.12; H, 5.06; N, 8.88.

[1975] 6. Benzazepinone Derivatives and Related Compounds

General Procedure 6-A Alkylation of1-Amino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

[1976] Step A:1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one wasprepared according to the procedure of Ben-Ishai et al., Tetrahedron,1987, 43, 430.

[1977] Step B:1-Ethoxycarbonylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (2.0 g,100 M %) was dissolved in DMF (30 mL) and NaH (95%, 0.17 g, 100M %) wasadded in one portion. The reaction mixture was stirred for 1 hour andthen the appropriate alkyl iodide (300M %) was added and the mixture wasstirred for 12 hours. The reaction was poured into water and extractedwith ethyl acetate (3×). The ethyl acetate extracts were then washedwith water (3×) and brine (1×). Treatment with MgSO₄, rotoevaporation,and chromotography (30% EtOAc/hexanes) yielded1-ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onein 87% yield.

[1978] Step C:1-Ethoxycarbonylamino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one(1.0 g, 100M %) was suspended in 30 mL of 30% HBr/HOAc and heated to100° C. The reaction mixture was stirred for 5 hours at this temperatureand then the reaction was cooled and rotoevaporated to yield1-amino-3-alkyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one as thehydrobromide salt (100% yield).

General Procedure 6-B Alkylation of3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[1979] Step A: 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one wasprepared from α-tetralone using the methods described in Armstrong etal. Tetrahedron Letters. 1994, 35, 3239. The following compounds were asprepared by this procedure for use in the following steps:

[1980] 5-methyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (from4-methyl-α-tetralone (Aldrich)); and

[1981] 5,5-dimethyl-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(from 4,4-dimethyul-α-tetralone (Aldrich)).

[1982] Step B: 3-Amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (4.43 g,100M %) was suspended in t-butanol (30 mL) and BOC-anhydride (7.5 mL,130M %) was added dropwise. The reaction was stirred for 2 hours andthen it was rotoevaporated to a residue which was chromatographed with60% ethyl acetate/hexanes to yield BOC-protected3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 87% yield.

[1983] Step C: BOC-protected3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (1.5 g, 100M %) wasdissolved in DMF (20 mL) and NaH (95%, 0.13 g, 100M %) was added in oneportion. The reaction mixture was stirred for 1 hour and then theappropriate alkyl iodide (300M %) was added and stirring was continuedfor 12 hours. The reaction was poured into water and extracted withethyl acetate (3×). The ethyl acetate extracts were washed with water(3×) and then brine (1×). Treatment with MgSO₄, rotoevaporation, andchromatography (30% EtOAc/hexanes) yielded a BOC-protected3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 80% yield.

[1984] Step D: The BOC-protected3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (1.0 g, 100M %)was suspended in 30 mL of 1:1 CH₂Cl₂/triflouroacetic acid and themixture was stirred for 4 hours. The reaction was then rotoevaporated toyield the 3-amino-1-alkyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100%yield).

Example 6-A Synthesis of3-Amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[1985] Step A: 3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-onewas prepared from 4-methyl-α-tetralone using the methods described inArmstrong et al. Tetrahedron Letters. 1994, 35, 3239.

[1986] Step B: 3-Amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(9.3 g 100M %) was dissolved in dioxane (300 mL) and the solution waschilled to 0° C. BOC-anhydride (13.89 g 130M %) was added and the icebath was removed allowing the solution to come to room temperature andstirring was continued for 16 hours. The solution was rotory evaporatedto remove dioxane to provide an off white solid. This solid wasrecrystallized from CHCl₃ to yield BOC-protected3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 55% yield.

[1987] Step C: BOC-protected3-amino-5-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100 M %) wasdissolved in DMF (20 mL) and NaH (95%, 100 M %) was added in one portionand the reaction mixture was stirred for 1 hour. Methyl iodide (300 M %)was added and this mixture was stirred for 12 hours. The reaction wasthen poured into water and extracted with ethyl acetate (3×) thenbackwashed with water (3×) and then brine (1×). Treatment with MgSO₄,rotoevaporation, and chromatography (5% MeOH/CH₂Cl₂) yieldedBOC-protected3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 75%yield.

[1988] Step D: BOC-protected3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (100 M %)was suspended in 30 mL of 1:1 CH₂Cl₂/triflouroacetic acid. The reactionmixture was stirred for 4 hours. The reaction was then rotoevaporated toyield 3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(100% yield).

Example 6-B Synthesis of5-(L-Alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-oneHydrochloride

[1989] Following the procedure of Example 7-I and using5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride(Example 6-C), the title compound was prepared.

Example 6-C Synthesis of5-Amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one Hydrochloride

[1990] Step A: Following General Procedure 5-A and usingN-t-Boc-5-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-6-one (GeneralProcedure 6-B, following by Boc protection) and methyl iodide,N-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one wasprepared.

[1991] Step B: Following General Procedure 8-N and usingN-t-Boc-5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one, thetitle compound was prepared.

Example 6-D Synthesis of3-(S)-Amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[1992] Step A:3-(S)-Amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was preparedfrom N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich) usingthe method of R. J. DeVita et al., Bioorganic and Medicinal ChemistryLett. 1995, 5(12)1281-1286.

[1993] Step B: Following General Procedure 5-A and using the productfrom Step A, the title compound was prepared.

Example 6-E Synthesis of3-(S)-Amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[1994] Step A:3-(S)-Amino-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one was preparedfrom N-Boc-serine (Bachem) and 2-fluoro-1-nitrobenzene (Aldrich) usingthe method of R. J. DeVita et al., Bioorganic and Medicinal ChemistryLett. 1995, 5(12)1281-1286.

[1995] Step B: Following General Procedure 5-A and using the productfrom Step A, the title compound was prepared.

Example 6-F Synthesis of3-(S)-Amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[1996] The title compound was prepared from N-Boc-cystine (Novabio) and2-fluoro-1-nitrobenzene (Aldrich) using the method of R. J. DeVita etal., Bioorganic and Medicinal Chemistry Lett. 1995, 5(12) 1281-1286,followed by General Procedure 5-A.

Example 6-1 Synthesis of1-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

[1997] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and1-amino-3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one, the titlecompound was prepared. The reaction was monitored by tlc on silica gel(Rf=0.15 in ethyl acetate) and purification was by flash chromatographyusing ethyl acetate as the eluant.

[1998] NMR data was as follows:

[1999]¹H-nmr (CDCl₃; 2 diasteromers): δ=8.10 (m, 1H), 7.58 (d, 0.5H),7.42 (d, 0.5H), 7.05 (m, 4H0, 6.65 (m, 3H), 6.29 (m, 1H), 4.80 (t, 1H),4.20 (m, 1H), 3.36 (s, 0.5H), 3.34 (s, 0.5H), 3.26 (bd, 2H), 3.10 (m,2H), 3.01 (s, 3H), 2.98 (s, 3H), 1.36 (d, 3H), 1.29 (s, 3H).

[2000]¹³C-nmr (CDCl₃; 2 diasteromers): δ=168.2, 167.9, 165.3, 165.2,165.1, 164.9, 160.3, 160.1, 157.0, 156.8, 134.4, 134.3, 130.1, 129.9,129.0, 128.8, 126.0, 123.3, 122.5, 119.5, 119.1, 107.9, 107.8, 107.6,98.3, 98.0, 97.6, 47.6, 47.4, 44.6, 44.5, 43.7, 43.6, 38.0, 37.8, 30.6,30.5, 26.6, 14.6, 14.1.

[2001] C₂₂H₂₃N₃O₃F₂ (MW=415.44); mass spectroscopy (M⁺) 415.

Example 6-2 Synthesis of1-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-3-ethyl-7-fluoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

[2002] Following General Procedure C above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and1-(S)-amino-3-ethyl-7-fluoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one(General Procedure 6-A), the title compound was prepared. Purificationwas by flash chromatography using 5% methanol/dichloromethane as theeluant.

[2003] NMR data was as follows:

[2004]¹H-nmr (CDCl₃): δ=7.8-7.7 (2×d, J=7 Hz, 1H0 7.1-7.0 (m, 2H), 6.8(m, % H), 6.2 (t, 1H), 4.7 (t, 1H0, 4.2 (m, 1H), 3.6-3.4 (m, 6H), 3.2(m, 2H), 1.5-1.3 (2×d, J=7 Hz, 3H), 1.1 (2×t, J=7 Hz, 3H).

[2005]¹³C-nmr (CDCl₃): δ=177.3, 172.5, 172.1, 169.6, 169.4, 163.8,160.5, 126.3, 126.2, 125.9, 125.8, 117.4, 117.2, 117.1, 116.9, 113.7,113.4, 112.4, 112.3, 112.1, 112.0, 103.0, 102.9, 102.7, 102.6, 102.2.,53.3, 51.7, 51.4, 49.2, 49.0, 44.8, 44.5, 42.6, 42.5, 42.4, 42.3, 32.2,19.0, 13.0, 12.9.

[2006] C₂₃H₂₄N₃O₃F₃ (MW=447.19); mass spectroscopy (MH⁺) N/A.

Example 6-4 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2007] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (General Procedure6-B), the title compound was prepared. The reaction was monitored by tlcon silica gel (Rf=0.15 in 12% methanol/dichloromethane) and purificationwas by flash chromatography using 12% methanol/dichloromethane as theeluant.

[2008] NMR data was as follows:

[2009]¹H-nmr (CDCl₃): δ=9.87 (s, 1H), 8.28 (d, 1H), 8.11 (d, 1H),7.30-6.96 (m, 7H), 4.23 (m, 1H), 4.18 (m, 1H), 3.49 (s, 2H), 2.68 (m,2H), 2.24 (m, 1H), 1.97 (m, 1H), 1.15 (s, 3H).

[2010]¹³C-nmr (CDCl₃): δ=171.95, 171.54, 189.00, 160.74, 141.06, 138.01,133.91, 129.90, 127.84, 125.58, 122.41, 112.79, 112.46, 102.23, 49.06,48.47, 41.67, 35.50, 28.39, 18.99.

[2011] C₂₁H₂₁N₃O₃F₂ (MW=401.42); mass spectroscopy (MH⁺) 402.

Example 6-5 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

[2012] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1-benzyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (GeneralProcedure 6-B), the title compound was prepared. Purification was byflash chromatography.

[2013] NMR data was as follows:

[2014]¹H-nmr (CDCl₃; 2 diasteromers): δ=7.20 (m, 9H), 6.73 (m, 3H), 5.26(dd, 1H), 4.76 (dd, 1H), 4.53 (p, 1H), 4.44 (m, 1H), 3.44 (s, 1H), 2.40(m, 3H) 1.83 (m, 1H), 1.28 (dd, 3H).

[2015]¹³C-nmr (CDCl₃; 2 diasteromers): δ=172.2, 172.1, 171.2, 171.1,170.0, 169.8, 1565.2, 165.0, 162.0, 140.7, 139.2, 137.4, 136.6, 129.9,129.1, 128.9, 128.7, 128.5, 128.1, 127.6, 124.0, 112.9, 112.8, 112.7,112.6, 103.4, 103.1, 102.8, 52.6, 52.5, 50.3, 49.5, 49.4, 43.1, 36.6,36.5, 28.7, 28.6, 19.4, 19.2.

[2016] C₂₈H₂₇N₃O₃F₂ (MW=491.54); mass spectroscopy (MH⁺) 491.

Example 6-7 Synthesis of3-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2017] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (GeneralProcedure 6-B), the title compound was prepared. The reaction wasmonitored by tlc on silica gel (Rf=0.21 in 3% methanol/dichloromethane)and purification was by flash chromatography using 3%methanol/dichloromethane as the eluant.

[2018] NMR data was as follows:

[2019]¹H-nmr (CDCl₃): δ=7.20 (m, 4H), 6.86 (d, 1H), 6.68 (m, 3H), 6.33(d, 1H), 4.40 (m, 3H), 3.46 (s, 2H), 3.36 (s, 3H), 2.78 (m, 1H), 2.57(m, 2H), 1.84 (m, 1H), 1.29 (d, 3H).

[2020]¹³C-nmr (CDCl₃): δ=171.5, 171.0, 169.4, 165.3, 165.1, 162.0,161.8, 141.9, 138.7, 135.1, 129.9, 128.6, 127.5, 123.4, 113.0, 112.5,103.6, 103.3, 103.0, 50.4, 49.5, 43.5, 36.7, 36.1, 28.8, 19.5.

[2021] C₂₂H₂₃N₃O₃F₂ (MW=415.44); mass spectroscopy (M⁺) 415.

Example 6-8 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2022] Following General Procedure C above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (preparedfrom 4-methyltetralone (Aldrich) using General Procedure 6-A), the titlecompound was prepared as a solid having a melting point of 115-119° C.Purification was by flash chromatography using 5%methanol/dichloromethane as the eluant.

[2023] NMR data was as follows:

[2024]¹H-nmr (CDCl₃): δ=7.2-7.0 (m, 5H), 6.8-6.5 (m, 4H), 4.5 (m, J=7Hz, 1H), 4.3 (m, J=4 Hz, 1H), 3.5 (s, 2H), 3.35 (s, 3H), 3.05 (m, J=6.5Hz, 1H), 2.2 (m, J=4.5 Hz, 1H), 1.95 (m, 1H), 1.3 (2×d, J=7 Hz, 6H).

[2025]¹³C-nmr (CDCl₃): δ=172.3, 166.4, 165.9, 164.4, 164.3, 160.0,159.9, 156.6, 139.9, 136.4, 133.6, 133.2, 122.8, 122.4, 120.5, 118.1,107.6, 107.3, 98.2, 97.9, 97.5, 95.5, 45.0, 44.9, 44.0, 43.9, 39.8,39.7, 37.9, 30.7, 30.7, 26.0, 14.0, 13.8, 12.4.

[2026] C₂₃H₂N₃O₃F₂ (MW=429.47); mass spectroscopy (MH⁺) 430.

Example 6-9 Synthesis of3-(3,5-Difluorophenylacetyl)amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2027] Following General Procedure C above usingN-(3,5-difluorophenyl)acetic acid (Oakwood) and3-amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Example6-A), the title compound was prepared as a solid having a melting pointof 185-187° C. Purification was by flash chromatography using 5%methanol/dichloromethane as the eluant.

[2028] NMR data was as follows:

[2029]¹H-nmr (CDCl₃): δ=7.4-7.1 (m, 4H), 6.9-6.6 (m, 4H), 4.3 (m, J=8Hz, 1H), 3.5 (s, 2H), 3.35 (s, 3H), 3.05 (m, J=6.5 Hz, 1H), 2.3 (m, J=8Hz, 1H), 1.95 (m, J=7 Hz, 1H), 1.3 (d, J=7.1 Hz, 3H).

[2030]¹³C-nmr (CDCl₃): δ=166.1, 163.8, 160.0, 159.8, 156.7, 156.5,136.4, 133.8, 133.7, 133.3, 122.8, 122.5, 120.5, 118.1, 107.6, 107.5,107.3, 107.2, 98.2, 97.8, 97.5, 45.1, 39.9, 38.0, 30.6, 26.0, 12.5.

[2031] C₂₀H₂₀N₂O₂F₂ (MW=358.39); mass spectroscopy (MH⁺) 359.

Example 6-10 Synthesis of3-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2032] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(Example 6-D), the title compound was prepared as a solid having amelting point of 110-114° C. The reaction was monitored by tlc on silicagel (Rf=0.38 in 10% methanol/dichloromethane) and purification was bysilica gel chromatography.

[2033] NMR data was as follows:

[2034]¹H-nmr (CDCl₃): δ=7.25 (d, J=4.2, 1H); 7.2 (m, 4H); 6.79 (d,J=5.7, 2H), 6.70 (t, J=2.1, 2.1, 1H); 6.61 (d, J=7.5, 1H); 4.83 (dq,J=7.2, 11.1, 7.5, 1H); 4.55 (dt, J=7.8, 9.3, 5.1, 2H); 4.11 (dd, J=9.9,11.1, 1H); 3.48 (s, 2H); 3.39 (s, 3H); 1.30 (d, J=6.6, 3H).

[2035]³C-nmr (CDCl₃): δ=167.3, 164.4, 160.0, 156.7, 145.2, 133.5, 131.2,122.9, 120.9, 118.5, 118.1, 107.6, 107.4, 98.3, 37.9, 37.6, 44.5, 44.0,37.8, 36.6, 14.0.

[2036] C₂₁H₂₁F₂N₃O₄ (MW=417); mass spectroscopy (MH⁺) 418.

Example 6-11 Synthesis of3-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2037] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(Example 6-E), the title compound was prepared as a solid having amelting point of 188-191° C. The reaction was monitored by tlc on silicagel (Rf=0.43 in 10% methanol/dichloromethane) and purification was byrecrystallization from ether/hexanes.

[2038] NMR data was as follows:

[2039]¹H-nmr (CDCl₃): δ=7.2 (m, 4H); 7.1 (m, 1H); 6.79 (dd, J=6.0, 6.6,2H); 6.71 (t, J=2.2, 2.2, 1H); 6.43 (dd, J=7.2, 8.8, 1H); 4.8 (m, 1H);4.6 (m, 2H); 4.2 (m, 2H); 3.50 (s, 2H); 1.31 (d, J=7.1, 3H); 1.16 (t,J=7.1, 7.1, 3H).

[2040]¹³C-nmr (CDCl₃): δ=172.9, 167.5, 164.8, 164.3, 146.6, 130.2,123.6, 121.4, 119.3, 118.5, 108.0, 107.7, 98.4, 44.9, 44.4, 39.0, 38.3,14.3.

[2041] C₂₂H₂₃F₂N₃O₄ (MW=431); mass spectroscopy (MH⁺) 432.

Example 6-12 Synthesis of3-(S)-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2042] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-(S)-amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(Example 6-F), the title compound was prepared as a solid having amelting point of 156-159° C. The reaction was monitored by tlc on silicagel (Rf=0.17 in 10% methanol/dichloromethane) and purification was bysilica gel chromatography.

[2043] NMR data was as follows:

[2044]¹H-nmr (CDCl₃): δ=7.63 (d, J=6.05, 1H); .7.43 (t, J=7.7, 7.7, 1H);7.2 (m, 3H); 6.79 (d, J=6.05, 2H); 6.54 (t, J=7.1, 7.1, 1H); 6.35 (d,J=7.7, 1H); 4.5 (m, 2H); 3.7 (m, 1H); 2.79 (t, J=11.0, 11.5, 1H); 1.29(d, J=6.6, 3H).

[2045]¹³C-nmr (CDCl₃): δ=172.9, 166.8, 165.8, 164.7, 141.4, 133.8,131.4, 126.2, 123.4, 122.7, 120.2, 108.0, 107.7, 98.4, 45.3, 44.5, 40.1,38.3, 33.8, 32.0, 14.3.

[2046] C₂₁H₂₁F₂N₃O₃S (MW=433); mass spectroscopy (MH⁺) 434.

Example 6-13 Synthesis of5-{N′-(3,5-Difluorophenylacetyl)-L-alaninyl}-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-6-one

[2047] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and5-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-6-one, the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.1, 5%MeOH/CHCl₃) and product was purified by chromatography (silica, 6%MeOH/CHCl₃).

[2048] NMR data was as follows:

[2049]¹H-nmr (d⁶-DMSO): δ=3.50 (d,2H); 9.55 (d, 1H). MW=429.47; massspectroscopy (M+) 429.

Example 6-14 Synthesis of5-{N′-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one

[2050] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride(Example 6-C), the title compound was prepared. The reaction wasmonitored by tlc (Rf=0.4, 5% MeOH/CHCl₃) and product was purified bychromatography (silica, 5% MeOH/CHCl₃) and crystallization fromacetonitrile.

[2051] NMR data was as follows:

[2052]¹H-nmr (d⁶-DMSO): δ=3.48 (d,2H); 4.25 (m,2H). MW=443.50; massspectroscopy (M+) 443.

Example 6-15 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one

[2053] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-onehydrochloride (Example 6-B), the title compound was prepared. Theproduct was purified by chromatography (silica, 3% MeOH/CHCl₃).

[2054] NMR data was as follows:

[2055]¹H-nmr (CDCl₃): δ=3.35 (d, 3H); 5.07 (d, 1H). MW=459.49; massspectroscopy (MH+) 460.

Example 6-16 Synthesis of1-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

[2056] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood) and1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one,the title compound was prepared. Purification was by LC 2000chromatography using ethyl acetate as the eluant.

[2057] C₂₇H₂₅N₃O₃F₂ (MW=477); mass spectroscopy (MH⁺) 478.1.

[2058] Anal. Calc. for C₂₇H₂₅N₃O₃F₂: C, 67.91; H, 5.28; N, 8.8. Found:C, 68.2; H, 5.35; N, 8.58.

Example 6-17 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2059] Following General Procedure C above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(General Procedure 6-B), the title compound was prepared. The reactionwas monitored by tlc (Rf=0.23, 30% EtOAc/hexanes) and the product waspurified by flash chromatography using EtOAc/hexanes as the eluant.

[2060] NMR data was as follows:

[2061]¹H-nmr (CDCl₃): δ=7.1-7.4 (m, 6H), 6.70 (m, 2H), 6.62 (t, 1H),4.46 (m, 1H), 4.39 (m, 1H), 3.64 (m, 1H), 3.57 (d, 2H), 2.52 (m, 1H),1.90 (m, 1H), 1.30 (m, 12H).

[2062]¹³C-nmr (CDCl₃): δ=167.3, 167.2, 165.7, 165.0, 164.9, 160.2,160.1, 156.9, 156.8, 136.4, 136.3, 134.5, 134.4, 123.4, 122.5, 122.0,119.7, 107.9, 107.8, 107.6, 97.9, 97.8, 45.5, 44.9, 44.9, 44.37, 44.34,40.0, 39.9, 37.9, 30.6, 36.7, 24.4, 14.2, 14.1, 9.15, 9.12.

[2063] C₂₄H₂₉N₃O₃F₂ (MW=457.52); mass spectroscopy (MH⁺) N/A.

Example 6-18 Synthesis of3-(3,5-Difluorophenylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2064] Following General Procedure C above usingN-(3,5-difluorophenyl)acetic acid (Oakwood) and3-amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(General Procedure 6-B), the title compound was prepared. The reactionwas monitored by tlc (Rf=0.28, 25% EtOAc/hexanes) and the product waspurified by flash chromatography using EtOAc/hexanes as the eluant.

[2065] NMR data was as follows:

[2066]¹H-nmr (CDCl₃): δ=7.38 (d, 1H), 7.20 (m, 4H), 6.81 (d, 2H), 4.42(m, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.29 (s, 2H), 2.45 (m, 1H), 1.38(s, 3H), 1.30 (t, 3H), 1.24 (s, 3H).

[2067]¹³C-nmr (CDCl₃): δ=166.2, 164.2, 160.3, 160.1, 157.0, 156.8,136.5, 136.3, 134.3, 123.4, 122.6, 122.1, 119.8, 107.9, 107.8, 107.7,107.6, 98.4, 98.0, 97.7, 45.7, 44.9, 40.0, 38.2, 36.6, 26.8, 24.5, 9.2.

[2068] C₂₂H₂₄N₂O₂F₂ (MW=386.45).

Example 6-19 Synthesis of3-(N′-(Cyclopentylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

[2069] Following General Procedure C above usingN-(cyclopentylacetyl)-L-alanine (Example D) and3-amino-1-ethyl-5,5-trimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one(General Procedure 6-B), the title compound was prepared. The reactionwas monitored by tlc (Rf=0.25, 30% EtOAc/hexanes) and the product waspurified by flash chromatography using EtOAc/hexanes as the eluant.

[2070] NMR data was as follows: ¹H-nmr (CDCl₃): δ=7.38 (d, 1H), 7.20 (m,1H), 6.42 (t, 1H), 4.43 (m, 1H), 3.93 (m, 1H), 3.83 (m, 1H), 2.42 (m,1H), 2.19 (s, 2H), 1.68 (m, 2H), 1.50 (m, 2H), 1.35 (s, 3H), 1.22 (t,3H), 1.21 (s, 3H), 1.05 (m, 2H).

[2071]¹³C-nmr (CDCl₃): δ=168.1, 168.0, 167.16, 167. 11, 165.7, 136.5,136.4, 123.3, 122.52, 122.50, 122.14, 122.1, 119.8, 119.7, 55.8, 45.6,45.5, 44.8, 44.7, 44.08, 44.05, 40.07, 40.01, 38.1, 32.5, 30.67, 30.65,27.9, 27.8, 26.8, 24.5, 20.3, 14.37, 14.32, 9.58, 9.2, 9.1.

[2072] C₂₄H₃₅N₃O₃ (MW=413.56); mass spectroscopy (MH⁺) N/A.

[2073] 7. Dibenzazepinone Derivatives and Related Compounds

General Procedure 7-A Preparation of5-Amino-7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Derivatives

[2074] Step A:

[2075] Following General Procedure 5-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one and an alkyl halide, the7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.

[2076] Step B: The 7-alkyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1eq.) was dissolved in THF and isoamylnitrite (1.2 eq.) was added. Themixture was cooled to 0° C. in an ice bath. NaHMDS (1.1 eq., 1M in THF)was added dropwise. After stirring for 1 hour or until the reaction wascomplete, the mixture was concentrated then acidified with 1N HCl andextracted with EtOAc. The organic portion was dried and concentrated toyield a crude product which was purified by silica gel chromatography.

[2077] Step C: The resulting oxime was dissolved in EtOH/NH₃ (20:1) andhydrogenated in a bomb using Raney nickel and hydrogen (500 psi) at 100°C. for 10 hours. The resulting mixture was filtered and concentrated toprovide an oil which was purified by silica gel chromatography to yieldthe title compound.

General Procedure 7-B Preparation of Fluoro-substituted5,7-dihydro-6H-dibenz[b,d]azepin-6-one Derivatives

[2078] A modification of the procedure of Robin D. Clark and Jahangir,Tetrahedron, Vol. 49, No. 7, pp. 1351-1356, 1993 was used. Specifically,an appropriately substituted N-t-Boc-2-amino-2′-methylbiphenyl wasdissolved in THF and cooled to −78° C. s-Butyl lithium (1.3M incyclohexane, 2.2 eq.) was added slowly so that the temperature remainedbelow −65° C. The resulting mixture was allowed to warm to −25° C. andwas stirred at that temperature for 1 hour. The mixture was cooled to−78° C. Dry CO₂ was bubbled through the mixture for 30 seconds. Themixture was allowed to warm to ambient temperature then was carefullyquenched with water. The mixture was concentrated under reduced pressurethen was adjusted to pH 3 with 1N HCl. The mixture was extracted withEtOAc and the organic portion was dried and concentrated to yield acrude material. The crude material was dissolved in methanol and thesolution was saturated with HCl. The mixture was heated at reflux for 12hours then was allowed to cool. The mixture was concentrated to providecrude lactam which was purified by chromatography or crystallization.

General Procedure 7-C Resolution of5-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2079] In a round bottom flask was added the racemic freebase amine (1.0eq.) in methanol followed by di-p-toluoyl-D-tartaric acid monohydrate(1.0 eq.). The mixture was concentrated in vacuo to a residue andredissolved in a moderate volume of methanol and allowed to stir at roomtemperature open to the atmosphere (8-72 hours). The solid was removedby filtration. The enantiomeric excess was determined by chiral HPLC(Chiracel ODR) using 15% acetonitrile and 85% H₂O with 0.1%trifluoroacetic acid and a flow rate of 1.0 mL/min at 35° C. Theresolved di-p-toluoyl-D-tartaric salt was then dissolved in EtOAc andsaturated NaHCO₃ until pH 9-10 was reached. The layers were separatedand the organic layer was washed again with saturated NaHCO₃, H₂O, andbrine. The organic layer was dried over MgSO₄ and the drying agent wasremoved by filtration. The filtrate was concentrated in vacuo. The freeamine was dissolved in MeOH and HCl (12M, 1.0 eq.) was added. The saltwas concentrated in vacuo and the resulting film was triturated withEtOAc. The HCl salt was filtered and rinsed with EtOAc. The ee wasdetermined by chiral HPLC.

Example 7-A Synthesis of5-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one HydrochlorideStep A—Synthesis of 7-Methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2080] A round bottom flask was charged with sodium hydride (0.295 g,7.46 mmol) in 9.0 ml of DMF and treated with5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.3 g, 6.22 mmol) (CAS #20011-90-9, prepared as described in Brown, et. al., TetrahedronLetters, No. 8, 667-670, (1971) and references cited therein). Afterstirring at 60° C. for 1 h, the solution was treated with methyl iodide(1.16 ml, 18.6 mmol) and stirring continued for 17 h with the exclusionof light. After cooling, the reaction was diluted with CH₂Cl₂/H₂O,washed with NaHSO₄ solution, H₂O, and dried over Na₂SO₄. Evaporation andflash chromatography (SiO₂, CHCl₃) gave 0.885 g (63%) of the titlecompound as a colorless solid.

[2081] NMR data was as follows:

[2082]¹H-nmr (CDCl₃): δ=7.62 (d, 2H), 7.26-7.47 (m, 6H), 3.51 (m, 2H),3.32 (s, 3H).

[2083] C₁₅H₁₃NO (MW=223.27); mass spectroscopy (MH+) 223.

[2084] Anal. Calcd for C₁₅H₁₃NO; C, 80.69 H, 5.87 N, 6.27. Found: C,80.11 H, 5.95 N, 6.23.

Step B—Synthesis of7-Methyl-5-oximo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2085] The compound isolated above (0.700 g, 3.14 mmol) was dissolved in20 ml of toluene and treated with butyl nitrite (0.733 ml, 6.28 mmol).The reaction temperature was lowered to 0° C. and the solution wastreated with KHMDS (9.42 ml, 0.5 M) under N₂ atmosphere. After stirringfor 1 h the reaction was quenched with a saturated solution of NaHSO₄,diluted with CH₂Cl₂ and separated. The organic layer was dried overNa₂SO₄ and the title compound purified by chromatography (SiO₂, 98:2CHCl₃/MeOH) giving 0.59 g (80%) as a colorless solid.

[2086] C₁₅H₁₂N₂O₂ (MW=252.275); mass spectroscopy (MH+) 252.

[2087] Anal. Calcd for C₁₅H₁₂N₂O₂; C, 71.42 H, 4.79 N, 11.10. Found: C,71.24 H, 4.69 N, 10.87.

Step C—Synthesis of5-Amino-7-Methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one Hydrochloride

[2088] The oxime isolated above (0.99 g, 3.92 mmol) was hydrogenated ina Parr apparatus at 35 psi over 10% Pd/C (0.46 g) in 3A ethanol. After32 h the reaction mixture was filtered through a plug of celite, thefiltrate evaporated to a foam and treated with a saturated solution ofHCl (g) in Et₂O. The resulting colorless solid was filtered, rinsed withcold Et₂O and vacuum dried to give 0.66 g (61%) of the title compound.

[2089] NMR data was as follows:

[2090]¹H-nmr (DMSOd6): δ=9.11 (bs, 3H), 7.78-7.41(m, 8H), 4.83 (s, 1H),3.25 (s, 3H).

[2091] C₁₅H₁₄N₂O HCl (MW=274.753); mass spectroscopy (MH+free base) 238.

[2092] Anal. Calcd for C₁₅H₁₄N₂O HCl; C, 65.57 H, 5.50 N, 10.19 Found:C, 65.27 H, 5.67 N, 10.13.

Example 7-B Synthesis of (S)- and(R)-5-(L-Alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneStep A—Synthesis of (S)- and(R)-5-(N-Boc-L-Alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2093] Boc-L-Alanine (0.429 g, 2.26 mmol) (Aldrich) was dissolved in THFand treated with HOBt hydrate (0.305 g, 2.26 mmol), and5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.45 g, 1.89mmol) (Example 7-A). The temperature was lowered to 0° C. and thereaction mixture treated with EDC (0.449 g, 2.26 mmol) (Alrich) andstirred 17 hours under N₂. The reaction mixture was evaporated, theresidue diluted with EtOAc/H₂O, washed 1.0 N HCl, sat. NaHCO₃, brine anddried over Na₂SO4. The diastereomers were separated on a Chiralcel ODcolumn using 10% IPA/heptane at 1.5 ml/minute.

[2094] Isomer 1: Retention time 3.37 minutes.

[2095] NMR data was as follows:

[2096]¹H-nmr (CDCl₃): δ=7.62-7.33 (m, 9H), 5.26 (d, 1H), 5.08 (m, 1H),4.34 (m, 1H), 3.35 (s, 3H), 1.49 (s, 9H), 1.40 (d, 3H).

[2097] Optical Rotation: [α]₂₀=−96 @589 nm (c=1, MeOH).

[2098] C₂₃H₂₇N₃O₄ (MW=409.489); mass spectroscopy (MH+) 409.

[2099] Anal. Calcd for C₂₃H₂₇N₃O₄; C, 67.46 H, 6.64 N, 10.26. Found: C,68.42 H, 7.02 N, 9.81.

[2100] Isomer 2: Retention time 6.08 minutes.

[2101] NMR data was as follows:

[2102]¹H-nmr (CDCl₃): δ=7.74 (bd, 1H), 7.62-7.32 (m, 8H), 5.28 (d, 1H),4.99 (m, 1H), 4.36 (m, 1H), 3.35 (s, 3H), 1.49 (s, 9H), 1.46 (d, 3H).

[2103] Optical Rotation: [α]₂₀=69 @589 n (c=1, MeOH).

[2104] C₂₃H₂₇N₃O₄ (MW=409.489); mass spectroscopy (MH+) 409.

[2105] Anal. Calcd for C₂₃H₂₇N₃O₄; C, 67.46 H, 6.64 N, 10.26. Found: C,67.40 H, 6.62 N, 10.02

Step B—Synthesis of (S)- and(R)-5-(L-Alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2106] The compounds isolated in Part A (each isomer separately) weredissolved in dioxane and treated with excess HCl (g). After stirring for17 hours, the title compounds were isolated as colorless solids afterevaporation and vacuum drying.

[2107] Isomer 1:

[2108] C₁₈H₁₉N₃O₂.HCl (MW=345.832); mass spectroscopy (MH+free base)309.

[2109] Optical Rotation: [α]₂₀=−55 @589 nm (c=1, MeOH).

[2110] Isomer 2:

[2111] C₁₈H₁₉N₃O₂.HCl (MW=345.832); mass spectroscopy (MH+free base)309.

[2112] Optical Rotation: [α]₂₀=80 @589 nm (c=1, MeOH).

Example 7-C Synthesis of (S)- and(R)-5-(L-Valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneStep A—Synthesis of (S)- and (R)-5-(N-Boc-L-Valinyl)-amino-7-methyl-S7-dihydro-6H-dibenz[b,d]azepin-6-one

[2113] Boc-L-Valine (0.656 g, 3.02 mmol) (Aldrich) was dissolved in THFand treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml, 6.05mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature waslowered to 0° C. and the reaction mixture treated with EDC (0.601 g,3.02 mmol)(Alrich) and stirred 17 hours under N₂. The reaction mixturewas evaporated, the residue diluted with EtOAc/H₂O, washed 1.0 N HCl,sat. NaHCO₃, brine and dried over Na₂SO₄. The diastereomers wereseparated on a Chiralcel OD column using 10% IPA/heptane at 1.5ml/minute.

[2114] Isomer 1: Retention time 3.23 minutes.

[2115] Optical Rotation: [α]₂₀=−120 @589 nm (c=1, MeOH).

[2116] C₂₅H₃₁N₃O₄ (MW=437.544); mass spectroscopy (MH+) 438

[2117] Isomer 2: Retention time 6.64 minutes.

[2118] Optical Rotation: [α]₂₀=50 @589 nm (c=1, MeOH).

[2119] C₂₅H₃₁N₃O₄ (MW=437.544); mass spectroscopy (MH+) 438

Step B—Synthesis of (S)- and(R)-5-(L-Valinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2120] The compounds isolated in Part A (each isomer separately) weredissolved in dioxane and treated with excess HCl (g). After stirring for17 hours, the title compounds were isolated as colorless solids afterevaporation and vacuum drying.

[2121] Isomer 1:

[2122] C₂₀H₂₃N₃O₂.HCl (MW=373.88); mass spectroscopy (MH+free base) 338.

[2123] Optical Rotation: [α]₂₀=−38 @589 nm (c=1, MeOH).

[2124] Isomer 2:

[2125] C₂₀H₂₃N₃O₂.HCl (MW=373.88); mass spectroscopy (MH+free base) 338.

[2126] Optical Rotation: [α]₂₀=97 @589 nm (c=1, MeOH).

Example 7-D Synthesis of (S)- and(R)-5-(L-tert-Leucine)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneStep A—Synthesis of (S)- and(R)-5-(N-Boc-L-tert-Leucinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2127] Boc-L-tert-Leucine (0.698 g, 3.02 mmol) (Fluka) was dissolved inTHF and treated with HOBt hydrate (0.408, 3.02 mmol), Dipea (1.05 ml,6.05 mmol) and 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (0.75 g, 2.75 mmol)(Example 7-A). The temperature waslowered to 0° C. and the reaction mixture treated with EDC (0.601 g,3.02 mmol) (Alrich) and stirred 17 hours under N₂. The reaction mixturewas evaporated, the residue diluted with EtOAc/H₂O, washed 1.0 N HCl,sat. NaHCO₃, brine and dried over Na₂SO₄. The diastereomers wereseparated on a Chiralcel OD column using 10% IPA/heptane at 1.5ml/minute.

[2128] Isomer 1: Retention time 3.28minutes.

[2129] Optical Rotation: [α]₂₀=−128 @589 nm (c=1, MeOH).

[2130] C₂₆H₃₃N₃O₄ (MW=451.571); mass spectroscopy (MH+) 452

[2131] Isomer 2: Retention time 5.52 minutes.

[2132] Optical Rotation: [α]₂₀=26 @589 nm (c=1, MeOH).

[2133] C₂₆H₃₃N₃O₄ (MW=451.571); mass spectroscopy (MH+) 452

Step B—Synthesis of (S)- and(R)-5-(L-tert-Leucinyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2134] The compounds isolated in Part A (each isomer separately) weredissolved in dioxane and treated with excess HCl (g). After stirring for17 hours, the title compounds were isolated as colorless solids afterevaporation and vacuum drying.

[2135] Isomer 1:

[2136] C₂₁H₂₅N₃O₂.HCl (MW=387.91); mass spectroscopy (MH+free base) 352.

[2137] Optical Rotation: [α]₂₀=−34 @589 nm (c=1, MeOH).

[2138] Isomer 2:

[2139] C₂₁H₂₅N₃O₂.HCl (MW=387.91); mass spectroscopy (MH+free base) 352.

[2140] Optical Rotation: [α]₂₀=108 @589 nm (c=1, MeOH).

Example 7-E Synthesis of5-(N-Boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one StepA—Synthesis of 5-Iodo-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2141] A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77mmol) (Example 7-A) and Et₃N (2.66 ml, 19.12 mmol) were stirred for 5.0minutes at −15° C. in CH₂Cl₂and treated with TMSI (1.36 ml, 9.54 mmol).After stirring for 15 minutes I₂ (1.81 g, 7.16 mmol) was added in asingle portion and the reaction allowed to warm to 5-10° C. over 3 h.The reaction was quenched with sat. Na₂SO₃, diluted with CH₂Cl₂ andseparated. The organics were washed with Na₂SO₃ and NaHSO₃ and driedover MgSO₄. After filtration, the organics were concentrated toapproximately 20 ml and diluted with an additional 20 ml of hexanes. Thetitle compound was isolated as a tan precipitate by filtration.

Step B—Synthesis of 5-Azido-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2142] The iodide isolate above was dissolved in DMF and treated with1.2 equivalents of NaN₃. After stirring 17 h at 23° C. the mixture wasdiluted with EtOAc/H₂O, separated, washed with brine and dried overMgSO₄. The title compound was triturated from hot EtOAc as a tan powder.

Step C—Synthesis of5-(N-Boc-Amino)-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one

[2143] The azide was dissolved in THF/H₂O and stirred at 23° C. for 17 hin the presence of 3.0 equivalents of Ph₃P. The reaction was dilutedwith 50% HOAc/toluene, separated, the aqueous layer extracted withtoluene and evaporated to an oily residue. This was taken to pH 7.0 bythe addition of 1 N NaOH, the resulting HOAc salt was collected andvacuum dried. Finally, the compound was treated with Boc anhydride (1.05equivalents) and Et₃N (2.1 equivalents) in THF. After stirring for 5 hat 23° C. the reaction was filtered and the title compound isolated as acolorless powder.

Example 7-F Synthesis of5-Amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride Step A—Synthesis of5-(N-Boc-Amino)-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2144] A solution of5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617mmol) (Example 7-E) in DMF was treated with Cs₂CO₃ (0.22 g, 0.678 mmol)and warmed to 60° C. To the reaction mixture was added1-iodo-2-methylpropane (0.078 ml, 0.678 mmol) and stirring continued for17 h. After cooling to 23° C. the mixture was diluted with CH₂Cl₂,washed with several portions of brine and dried over Na₂SO₄. The titlecompound was purified by chromatography (SiO₂, CHCl₃/MeOH 9:1).

[2145] C₂₃H₂₈N₂O₃ (MW=380.41); mass spectroscopy (MH+) 381

[2146] Anal. Calcd for C₂₃H₂₈N₂O₃; C, 72.61 H, 7.42 N, 7.36. Found: C,72.31 H, 7.64 N, 7.17.

Step B—Synthesis of5-Amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2147] The compound isolated in Part A was deprotected in dioxanesaturated with gaseous HCl. The title compound was isolated as aslightly colored solid after evaporation and vacuum drying.

Example 7-G Synthesis of5-Amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride Step A—Synthesis of5-(N-Boc-Amino)-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2148] A solution of5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.03, 3.08 mmol)(Example 7-E) in DMF was treated with Cs₂CO₃ (1.10 g, 3.39 mmol) andwarmed to 60° C. To the reaction mixture was added bromomethyl acetate(0.321 ml, 3.39 mmol) (Aldrich) and stirring continued for 17 h. Aftercooling to 23° C. the mixture was diluted with CH₂Cl₂, washed withseveral portions of brine and dried over Na₂SO₄. The title compound waspurified by chromatography (SiO₂, CHCl₃).

[2149] C₂₂H₂₄N₂O₅ (MW=396.44); mass spectroscopy (MH+) 397

[2150] Anal. Calcd for C₂₂H₂₄N₂O₅; C, 66.65 H, 6.10 N, 7.07. Found: C,66.28 H, 5.72 N, 6.50.

Step B—Synthesis of5-Amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2151] The compound isolated in Part A was deprotected in dioxanesaturated with gaseous HCl. The title compound was isolated as-acolorless solid after evaporation and vacuum drying.

[2152] C₁₇H₁₆N₂O₃ HCl (MW=332.78); mass spectroscopy (MH+free base) 297.

Example 7-H Synthesis of5-Amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride Step A—Synthesis of5-(N-Boc-Amino)-7-(3,3-dimethyl-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2153] A solution of5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.2 g, 0.617mmol) (Example 7-E) in. DMF was treated with Cs₂CO₃ (0.3 g, 0.925 mmol)and warmed to 60° C. To the reaction mixture was added1-chloro-3,3-dimethyl-2-butanone (0.096 ml, 0.74 mmol) (Aldrich) andstirring continued for 17 h. After cooling to 23° C., the mixture wasdiluted with CH₂Cl₂, washed with several portions of brine and driedover Na₂SO₄. The title compound was isolated as a colorless solid.

[2154] C₂₅H₃₀N₂O₄ (MW=422.522); mass spectroscopy (MH+) 423

Step B—Synthesis of5-Amino-7-(3,3-dimethyl-2-butanonyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2155] The compound isolated in Part A was deprotected in dioxanesaturated with gaseous HCl. The title compound was isolated as acolorless solid after evaporation and vacuum drying.

Example 7-1 Synthesis ofL-Alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2156] Step A: Following General Procedure D and using N-t-Boc-L-alanineand 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,N-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onewas prepared.

[2157] Step B: Following General Procedure 8-N and using theN-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,the title compound was prepared. Other substitutedN-t-Boc-L-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onescan also be prepared by this procedure.

Example 7-J Synthesis ofL-Valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2158] Step A: Following General Procedure D and using N-t-Boc-L-valineand 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,N-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onewas prepared.

[2159] Step B: Following General Procedure 8-N and using theN-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one,the title compound was prepared. Other substitutedN-t-Boc-L-valinyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onescan also be prepared by this procedure.

Example 7-K Synthesis of5-Amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2160] Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and 1-chloro-4-phenylbutane (Aldrich), the title compoundwas prepared.

Example 7-L Synthesis of5-Amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2161] Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and (bromomethyl)cyclopropane (Aldrich), the titlecompound was prepared.

Example 7-M Synthesis of5-Amino-7-(2′,2′,2′-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2162] Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and 1-bromo-2,2,2-trifluoroethane (Aldrich), the titlecompound was prepared.

Example 7-N Synthesis of5-Amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2163] Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and bromocyclohexane (Aldrich), the title compound wasprepared.

Example 7-O Synthesis of5-(L-Alaninyl)amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2164] Step 1: 2-Bromo-5-fluorotoluene was stirred in THF at −78C.s-BuLi (1.05 eq., 1.3 M in cyclohexane) was slowly added and the mixturewas stirred for 45 minutes. Trimethylborate (1.5 eq) was added and themixture was allowed to warm to ambient temperature. After stirring for 1hour, pinacol (2 eq.) was added. The mixture was stirred for 16 hoursthen was concentrated under reduced pressure. The resulting residue wasslurried in CH₂Cl₂ and filtered through Celite. The filtrate wasconcentrated to yield an oil which was purified by chromatography ondeactivated silica gel (Et₃N) to yield the arylboronate ester.

[2165] Step 2: 2-Bromoaniline (1 eq.) and di-t-butyl-dicarbonate (1.1eq.) were stirred at 80° C. for 20 hours. The resulting mixture wasallowed to cool and was directly distilled using house vacuum to provideN-t-Boc-2-bromoaniline.

[2166] Step 3: N-t-Boc-2-bromoaniline (Step 2, 1 eq.), the arylboronateester (Step 1, 1.1 eq.), K₂CO₃ (1.1 eq.) andtetrakis(triphenylphosphine)palladium(0) (0.02 eq) were stirred in 20%water/dioxane under nitrogen. The solution was heated at reflux for 10hours. The mixture was allowed to cool then was concentrated. Theresulting residue was partitioned between water and chloroform. Theorganic portion was dried and concentrated to yield an oil which waspurified by silica gel chromatography using 1:1 CH₂Cl₂/hexanes.

[2167] Step 4: Following General Procedure 7-B and using the substitutedbiphenyl from step 3, the9-fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.

[2168] Step 5: 9-Fluoro-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1 eq.,Step 4), cesium carbonate (1.1 eq., Aldrich) and methyl iodide (1.1 eq.,Aldrich) were stirred in dry DMF at ambient temperature for 16 hours.The mixture was concentrated under reduced pressure to provide a residuewhich was partitioned between EtOAc and water. The organic portion wasdried and concentrated to yield an oil which was purified by silica gelchromatography to9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

[2169] Step 6: Following General Procedure 7-A, Step B and9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one from Step 5,5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one wasprepared.

[2170] Step 7: Following the procedure of Example 7-I and using5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one fromStep 6, the title compound was prepared.

Example 7-P Synthesis of5-(L-Alaninyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2171] Following the procedure of Example 7-O and using2-bromo-4-fluoroaniline (Step 2, Lancaster) and o-tolylboronic acid(Step 3, Aldrich), the title compound was prepared.

Example 7-Q Synthesis of5-(L-Alaninyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2172] Following the procedure of Example 7-O and using2-bromo-4-fluorotoluene (Step 1), the title compound was prepared.

Example 7-R Synthesis of5-(L-Alanyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2173] Following the procedure of Example 7-I and using5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-L), the title compound was prepared.

Example 7-S Synthesis of5-(L-Alaninyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2174] Following the procedure of Example 7-I and using5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example7-K), the title compound was prepared.

Example 7-T Synthesis of5-(L-Valinyl)amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2175] Following the procedure of Example 7-J and using5-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-L), the title compound was prepared.

Example 7-U Synthesis of5-(L-Valinyl)amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2176] Following the procedure of Example 7-J and using5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example7-U), the title compound was prepared.

Example 7-V Synthesis of5-(L-Valinyl)amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2177] Step A: Following General Procedure 7-A and using5,7-dihydro-6H-dibenz[b,d]azepin-6-one (prepared as described in Brown,et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and referencescited therein) and 1-bromohexane (Aldrich),5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one was prepared.

[2178] Step B: Following the procedure of Example 7-J and using5-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, the titlecompound was. prepared.

Example 7-W Synthesis of5-(L-Valinyl)amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2179] Following the procedure of Example 7-J and using5-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (asprepared in Example 7-Q, the title compound was prepared.

Example 7-X Synthesis of5-(L-Valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2180] Following the procedure of Example 7-J and using the5-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (asprepared in Example 7-P), the title compound was prepared.

Example 7-Y Synthesis of5-(L-Valinyl)amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2181] Following the procedure of Example 7-J and using the5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (asprepared in Example 7-O), the title compound was prepared.

Example 7-Z Synthesis of(5-Amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d]azepin-6-one

[2182] The 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-A) was dissolved in a 1:1 mixture ofEtOAc/HOAc. 5% Rh/C was added and the mixture was stirred at 60° C.under 60 psi of hydrogen. After 3 days, the mixture was filtered and thefiltrate was concentrated to provide an oil which was purified bySCX-cation exchange chromatography to yield the title compound.

Example 7-AA Synthesis of5-(S)-Amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneHydrochloride

[2183] Following General Procedure 7-C using racemic5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 eq.) anddi-p-toluoyl-D-tartaric acid monohydrate (1.0 eq.) in methanol, thetitle compound was prepared as a solid. The product was collected byfiltration. Enantiomeric excess was determined by chiral HPLC.

[2184] Desired enantiomer 1: retention time of 9.97 minutes.

[2185] Undesired enantiomer 2: retention time of 8.62 minutes.

[2186] NMR data was as follows:

[2187]¹H-nmr (CDCl₃): δ=9.39 (s, 2H), 7.75-7.42 (m, 8H), 4.80 (s, 1H),3.30 (s, 3H).

[2188] C₁₅H₁₅ClN₂O (MW=274.75); mass spectroscopy (MH⁺) 239.1.

[2189] Anal Calcd for C₁₅H₁₅ClN₂O₃; C, 65.57; H, 5.50; N, 10.20; Found:C, 65.51, H, 5.61; N, 10.01.

Example 7-1 Synthesis of 5-(S)-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2190] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride(Example 7-A), the title compound was prepared as a colorless solid. Thediastereomers were purified by HPLC (Bulk OD-25) using 15% EtOH inheptane as eluent and a flow rate of 1.5 ml/min.

[2191] Isomer 1: retention time of 11.4 minutes.

[2192] NMR data was as follows:

[2193]¹H-nmr (CDCl₃): δ=7.62-7.33 (m, 8H), 6.79 (m, 2H), 6.71 (m, 1H),6.47 (m, 1H), 5.24 (d 1H), 4.70 (m, 1H), 3.48 (s, 2H), 3.34 (s, 3H),1.42 (d, 3H).

[2194] Optical Rotation: [α]₂₀=−125 @589 nm (c=1, MeOH).

[2195] C₂₆H₂₃F₂N₃O₃ (MW=463.49); mass spectroscopy (MH+) 463.

[2196] Anal. Calcd for C₂₆H₂₃F₂N₃O₃; C, 67.38 H, 5.00 N, 9.06. Found: C,67.49 H, 5.06 N, 8.93.

Example 7-2 Synthesis of5-(S)-[N′-((S)-3,5-Difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneand5-(S)-[N′-((R)-3,5-Difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2197] Following General Procedure D above using 3,5-difluoromandelicacid and5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-B), the title compound was prepared as acolorless solid. The diastereomers were purified by flash chromatographyusing 98:2 CHCl₃/MeOH.

[2198] Isomer 1:

[2199] NMR data was as follows:

[2200]¹H-nmr (CDCl₃): δ=7.67 (d, 1H), 7.60-7.28 (m, 8H), 7.15 (d, 1H),6.98 (m, 2H), 6.74 (m, 1H), 5.21 (d, 1H), 4.94 (d, 1H), 4.61 (m, 1H),4.56 (m, 1H), 3.34 (s, 3H), 1.42 (d, 3H).

[2201] Optical Rotation: [α]₂₀=−121 @589 nm (c=1, MeOH).

[2202] C₂₆H₂₃F₂N₃O₄ (MW=479.488); mass spectroscopy (MH+) 479.

[2203] Anal. Calcd for C₂₆H₂₃F₂N₃O₄; C, 65.13 H, 4.83 N, 8.76. Found: C,65.42 H, 4.73 N, 8.65.

[2204] Isomer 2:

[2205] NMR data was as follows:

[2206]¹H-nmr (CDCl₃): δ=7.78 (d, 1H), 7.66 (d, 1H), 7.54-7.28 (m, 8H),6.89 (m, 2H), 6.71 (m, 2H), 5.22 (d 1H), 4.92 (m, 1H), 4.65 (m, 1H),4.01 (m, 1H), 3.37 (s, 3H), 1.39 (d, 3H).

[2207] Optical Rotation: [α]₂₀=−146 589 nm (c=1, MeOH).

[2208] C₂₆H₂₃F₂N₃O₄ (MW=479.488); mass spectroscopy (MH+) 479.

[2209] Anal. Calcd for C₂₆H₂₃F₂N₃O₄; C, 65.13 H, 4.83 N, 8.76. Found: C,65.18, 4.82, 8.65.

Example 7-3 Synthesis of 5-(S)-[N′-(3,5-Difluorophenyl-α-ketoacetyl)-L-alaninylamino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2210] Following the Jones oxidation procedure (Fieser and Fieser,Reagents for Organic Synthesis, Vol. 1, p. 142) using5-(S)-[((SIR)-3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-2), the title compound was prepared as a colorless solid.

[2211] NMR data was as follows:

[2212]¹H-nmr (CDCl₃): δ=7.92 (m, 2H), 7.61-7.35 (m, 8H), 7.08 (m, 1H),5.31 (d, 1H), 4.74 (m, 1H), 3.38 (s, 3H), 1.56 (d, 3H).

[2213] C₂₆H₂₁F₂N₃O₄ (MW=477.472); mass spectroscopy (MH+) 477.

[2214] Anal. Calcd for C₂₆H₂₁F₂N₃O₄; C, 65.40 H, 4.43 N, 8.80. Found: C,65.66 H, 4.71 N, 8.54.

Example 7-4 Synthesis of5-(S)-[N′-(3,5-difluorophenylacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2215] Following General Procedure D above using3,5-difluorophenylacetic acid and5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-C), the title compound was prepared as acolorless solid. The product was purified by flash chromatography using98:2 CHCl₃/MeOH.

[2216] NMR data was as follows:

[2217]¹H-nmr (CDCl₃): δ=7.54-7.25 (m, 8H), 6.74 (m, 2H), 6.74 (m, 2H),6.70 (m, 1H), 6.49 (d, 1H), 5.26 (d, 1H), 4.49 (m,1H), 3.43 (s, 2H),3.35 (s, 3H), 2.06 (m, 1H), 0.91 (m, 6H).

[2218] Optical Rotation: [α]₂₀=−144 @589 nm (c=1, MeOH).

[2219] C₂₈H₂₇F₂N₃O₃ (MW=491.543); mass spectroscopy (MH+) 490.9

[2220] Anal. Calcd for C₂₈H₂₇F₂N₃O₃; C, 68.42 H, 5.54 N, 8.55. Found: C,68.51 H, 5.82, N, 8.61.

Example 7-5 Synthesis of5-(S)-[N′-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2221] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood) and5-(S)-[L-tert-leucinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-D), the title compound was prepared as acolorless solid. The product was purified by flash chromatography using98:2 CHCl₃/MeOH.

[2222] NMR data was as follows:

[2223]¹H-nmr (CDCl₃): δ=7.58-7.36 (m, 9H), 6.80 (m, 2H), 6.72 (m, 1H),6.25 (d, 1H), 5.27 (d, 1H), 4.52 (d, 1H), 3.53 (s, 2H), 3.35 (s, 3H),0.97 (m, 9H).

[2224] Optical Rotation: [α]₂₀=−137 @589 nm (c=1, MeOH).

[2225] C₂₉H₂₉F₂N₃O₄ (MW=505.57); mass spectroscopy (MH+) 504.9

[2226] Anal. Calcd for C₂₈H₂₇F₂N₃O₄.H₂O; C, 66.52 H, 5.92 N, 8.02.Found: C, 66.39 H, 5.76, N, 7.79.

Example 7-6 Synthesis of5-(S)-[N′-((S)-3,5-Difluorophenyl-α-hydroxyacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2227] Following General Procedure D above using(S)-3,5-difluoromandelic acid and5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-C), the title compound was prepared as acolorless solid. The product was purified by flash chromatography using98:2 CHCl₃/MeOH.

[2228] NMR data was as follows:

[2229]¹H-nmr (CDCl₃): δ=7.78 (d, 1H), 7.53-7.25 (m, 8H), 6.86 (m, 2H),6.71 (m, 2H), 5.22 (d, 1H), 4.76 (s, 1H) 4.43 (m,1H), 3.34 (s, 3H), 2.08(m, 1H), 0.91 (m, 6H).

[2230] C₂₈H₂₇F₂N₃O₄ (MW=507.542); mass spectroscopy (MH+) 506.9

[2231] Anal. Calcd for C₂₈H₂₇F₂N₃O₄; C, 66.26 H, 5.32 N, 8.27. Found: C,66.08 H, 5.62, N, 7.97.

Example 7-7 Synthesis of5-(S)-[N′-((S)-3,5-difluorophenyl-α-hydroxyacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2232] Following General Procedure D above using(S)-3,5-difluoromandelic acid and5-(S)-[L-tert-leucinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-D), the title compound was prepared as acolorless solid. The product was purified by flash chromatography using98:2 CHCl₃/MeOH.

[2233] NMR data was as follows:

[2234]¹H-nmr (CDCl₃): δ=7.67 (d, 1H), 7.54-7.25 (m, 8H), 6.83 (m, 2H),6.69 (m, 2H), 5.22 (d, 1H), 4.74 (s, 1H) 4.44 (d, 1H), 3.35 (s, 3H),0.97 (m, 9H).

[2235] C₂₉H₂₉F₂N₃O₄ (MW=521.569); mass spectroscopy (MH+) 520.9

[2236] Anal. Calcd for C₂₉H₂₉F₂N₃O₄; C, 66.78 H, 5.60 N, 8.06. Found: C,66.56 H, 5.85, N, 7.83.

Example 7-8 Synthesis of5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2237] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and5-amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-G), the title compound was prepared as acolorless solid. The product was purified by flash chromatography.

[2238] NMR data was as follows:

[2239]¹H-nmr (CDCl₃): δ=7.61-7.215 (m, 8H), 6.76 (m, 2H), 6.68 (m, 1H),6.53 and 6.40 (two d, 1H), 5.32 (d, 1H), 4.71 (m, 1H) 4.37 (m, 2H), 3.69(s, 3H), 1.49 and 1.39 (two d, 3H).

[2240] C₂₈H₂₅F₂N₃O₅ (MW=521.518); mass spectroscopy (MH+) 522

[2241] Anal. Calcd for C₂₈H₂₅F₂N₃O₅.1.5 mol H₂O; C, 61.30 H, 4.55 N,7.65. Found: C, 61.30 H, 4.53, N, 7.68.

Example 7-9 Synthesis of5-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-7-(methylcarboxylate)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2242] Following General Procedure II-A, Method B and using5-[(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-8), the title compound was prepared as a colorless solid. Theproduct was purified by flash chromatography.

[2243] C₂₇H₂₃F₂N₃O₅ (MW=507.49); mass spectroscopy (MH+) 508

[2244] Anal. Calcd for C₂₇H₂₃F₂N₃O₅.2 mol H₂O; C, 59.66 H, 4.23 N, 7.72.Found: C, 59.88 H, 4.29, N, 7.66.

Example 7-10 Synthesis of5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(3,3-dimethyl-2-butanoyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2245] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and5-amino-7-(3,3-dimethyl-2-butanoyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-H), the title compound was prepared as acolorless solid. The product was purified by flash chromatography.

[2246] NMR data was as follows:

[2247]¹H-nmr (CDCl₃): δ=7.57 (m, 3H), 7.41 (m, 5H), 7.14 (m, 1H), 6.78(m, 2H), 6.68 (m, 1H), 6.44 and 6.26 (two d, 1H), 5.34(d, 1H), 4.68 (m,1H) 4.59 (m, 2H), 3.52 and 3.47 (two s, 2H), 1.52 and 1.42 (two d, 3H),1.23 (s, 9H).

[2248] C₃₁H₃₁F₂N₃O₄ (MW=547.599); mass spectroscopy (MH+) 548

[2249] Anal. Calcd for C₃₁H₃₁F₂N₃O₄.0.5 mol H₂O; C, 66.89 H, 5.59 N,7.54. Found: C, 66.52 H, 5.73, N, 7.18.

Example 7-11 Synthesis of5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(morpholinylacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2250] Following General Procedure D using5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-(methylcarboxylate)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-9) and morpholine (Aldrich), the title compound was preparedas a colorless foam. The product was purified by flash chromatography.

[2251] NMR data was as follows:

[2252]¹H-nmr (CDCl₃): δ=7.57-7.37 (m, 8H), 6.81-6.69 (m, 3H), 5.35 (m,1H), 4.73-4.67 (m, 2H), 4.17 (m, 1H), 3.66-3.26 (m, 10 H), 1.46 and 1.40(two d, 3H).

[2253] C₃₁H₃₀F₂N₄O₅ (MW=576.592); mass spectroscopy (MH+) 577

[2254] Anal. Calcd for C₃₁H₃₀F₂N₄O₅.0.5 mol H₂O; C, 63.57 H, 5.12 N,9.56. Found: C, 63.41 H, 5.51, N, 8.92.

Example 7-12 Synthesis of5-(S)-(N′-((S)-(+)-2-Hydroxy-3-methylbutyryl)-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2255] Following General Procedure H using(S)-(+)-2-hydroxy-3-methylbutyric acid (Aldrich) and5-5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-B), the title compound was prepared as a white solid. Theproduct was purified by silica gel chromatography using gradient elutionof MeOH/CH₂Cl₂ (1:99-3:97).

[2256] NMR data was as follows:

[2257]¹H-nmr (CDCl₃): δ=7.94 (d, J=7.0 Hz, 1H), 7.55-7.22 (m, 9H), 5.25(d, J=7.5 Hz, 1H), 4.79-4.75 (m, 1H), 3.83 (d, J=3.1 Hz, 1H), 3.78 (brs, 1H), 3.32 (s, 3H), 2.08-2.01 (m, 1H), 1.36 (d, J=7.0 Hz, 3H), 0.83(d, J=7.0 Hz, 3H), 0.76 (d, J=6.5 Hz, 3H).

[2258] C₂₃H₂₇N₃O₄ (MW=409.48); mass spectroscopy (MH⁺) 410.4.

[2259] Anal Calcd for C₂₃H₂₇N₃O₄, C, 67.46; H, 6.65, N, 10.26; Found: C,67.59; H, 6.66; N, 10.34.

Example 7-13 Synthesis of5-[N′-Cyclopentyl-α-hydroxyacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2260] Following General Procedure D above usingcyclopentyl-α-hydroxyacetic acid (Example P) and5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-C), the title compound was prepared as acolorless solid. The product was purified by flash chromatography using98:2 CHCl₃/MeOH.

[2261] C₂₇H₃₃N₃O₄ (MW=463.5); mass spectroscopy (MH+) 464.

[2262] Anal. Calcd for C₂₇H₃₃N₃O₄; C, 69.96 H, 7.18 N, 9.06. Found: C,69.72 H, 6.99, N, 8.91.

Example 7-14 Synthesis of5-(S)-(N′-((S)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneand5-(S)-(N′-((R)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2263] Following General Procedure H using 2-hydroxy-3,3-dimethylbutyricacid (Aldrich) and5-(S)-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-B), the title compound was prepared as a white solid. Theproduct was purified by silica gel chromatography using gradient elutionof MeOH/CH₂Cl₂ (1:99-3:97).

[2264] NMR data for isomer 1 was as follows:

[2265]¹H-nmr (CDCl₃): δ=7.90 (d, J=6.6 Hz, 1H), 7.57-7.24 (m, 8H), 6.99(d, J=7.5 Hz, 1H), 5.24 (d, J=6.5 Hz, 1H), 4.83-4.76 (m, 1H), 3.69 (s,1H), 3.32 (s, 3H), 3.19 (br s, 1H), 1.39 (d, J=7.0 Hz, 3H), 0.96 (s,9H).

[2266] C₂₄H₂₉N₃O₄ (MW=423.51); mass spectroscopy (MH⁺) 424.1.

[2267] Anal Calcd for C₂₄H₂₉N₃O₄(isomer 1), C, 68.07; H, 6.90; N, 9.92;Found: C, 68.22, H, 7.04; N, 9.91.

[2268] NMR data for isomer 2 was as follows:

[2269]¹H-nmr (CDCl₃): δ=8.00-7.99 (m, 1H), 7.97-7.30 (m, 8H), 7.03-7.00(m, 1H), 5.25 (d, J=7.0 Hz, 1H), 4.82-4.75 (m, 1H), 3.69 (s, 1H), 3.33(s, 3H), 2.66 (br s, 1H), 1.48 (d, J=7.0 Hz, 3H), 0.98 (s, 9H).

[2270] C₂₄H₂₉N₃O₄ (MW=423.51); mass spectroscopy (MH⁺) 424.1.

[2271] Anal Calcd for C₂₄H₂₉N₃O₄(isomer 2), C, 68.07; H, 6.90; N, 9.92;Found: C, 67.77, H, 7.08; N, 9.66.

Example 7-15 Synthesis of5-[N′-Cyclopentyl-α-hydroxyacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2272] Following General Procedure D above usingcyclopentyl-α-hydroxyacetic acid (Example P) and5-(S)-[L-tert-leucinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-D), the title compound was prepared as acolorless solid. The product was purified by flash chromatography using98:2 CHCl₃/MeOH.

[2273] C₂₈H₃₅N₃O₄.(477.6); mass spectroscopy (MH+) 478.

[2274] Anal. Calcd for C₂₈H₃₅N₃O₄; C, 66.39 H, 5.57 N, 11.06. Found: C,66.33 H, 5.67, N, 10.89.

Example 7-16 Synthesis of5-[N′-Cyclopentyl-α-hydroxyacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2275] Following General Procedure D above usingcyclopentyl-α-hydroxyacetic acid (Example P) and5-(S)-[L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-B), the title compound was prepared as acolorless solid. The product was purified by flash chromatography using99:1 CHCl₃/MeOH.

[2276] NMR data was as follows:

[2277]¹H-nmr (CDCl₃): δ=7.78 (m, 2H), 7.62-7.28 (m, 8H), 7.08 and 6.99(two d, 1H), 5.27 (d, 1H), 4.78 (m, 1H), 4.06 (m, 1H), 3.34 (s, 3H),2.54 (m, 2H), 2.29 (m, 1H), 1.76-1.48 (m, 6H)1.43 (d, 3H).

[2278] C₂₅H₂₉N₃O₄.(435.52); mass spectroscopy (MH+) 436

[2279] Anal. Calcd for C₂₅H₂₉N₃O₄; C, 68.95 H, 6.71 N, 9.65. Found: C,69.06 H, 6.89, N, 9.51.

Example 7-17 Synthesis of5-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one

[2280] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and5-amino-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one hydrochloride(prepared using the compound of Example 7-E, followed by Boc removal asin Example 7-B, Step B), the title compound was prepared as a colorlesssolid. The product was purified by flash chromatography using 95:5CHCl₃/MeOH.

[2281] NMR data was as follows:

[2282]¹H-nmr (DMSO_(d6)): δ=8.86 (m, 1H), 8.75 (m, 1H), 8.49 (m, 1H),7.78-7.23 (m, 8H), 7.09 (m, 1H), 7.03 (m, 2H), 5.07 (m, 1H), 4.60 (m,1H), 3.55 (s, 2H), 1.32 (d, 3H).

[2283] C₂₅H₂₁F₂N₃O₃.(449.45); mass spectroscopy (MH+) 450.

[2284] Anal. Calcd for C₂₅H₂₁F₂N₃O₃; C, 66.81 H, 4.71 N, 9.35. Found: C,67.11 H, 4.84, N, 9.09.

Example 7-18 Synthesis of5-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2285] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and5-amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-F), the title compound was prepared as acolorless solid. The product was purified by flash chromatography using99:1 CHCl₃/MeOH.

[2286] NMR data was as follows:

[2287]¹H-nmr (CDCl₃): δ=7.58-7.33 (m, 4H), 7.40 (m, 4H), 6.81 (m, 2H),6.71 (m, 1H), 6.34 and 6.27 (two d, 1H), 5.22 (d 1H), 4.69 (m, 1H), 4.27(m, 1H), 3.52 (s, 2H), 3.33 (m, 1H), 1.52 and 1.42 (two d, 3H), 0.57 and0.29 (two d, 3H).

[2288] C₂₉H₂₉F₂N₃O₃ (MW=505.562); mass spectroscopy (MH+) 505.

[2289] Anal. Calcd for C₂₉H₂₉F₂N₃O₃; C, 68.89 H, 5.78 N, 8.31. Found: C,69.01 H, 6.02 N, 8.33.

Example 7-19 Synthesis of5-[N′-(2-Hydroxy-3-methylbutyryl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2290] Following General Procedure D above using2-hydroxy-3-methylbutyric acid (Aldrich) and5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-C), the title compound was prepared as acolorless solid. The product was purified by flash chromatography using98:2 CHCl₃/MeOH.

[2291] NMR data was as follows:

[2292]¹H-nmr (CDCl₃): δ=7.69-7.25 (m, 8H), 7.08 and 6.92 (two d, 1H),5.29 (d, 1H), 4.54 (m, 1H), 4.01 (m, 1H), 3.36 (s, 3H), 2.12 (m, 2H),0.99 (m, 6H) 0.83 (m, 6H).

[2293] C₂₅H₃₁N₃O₄.(437.537); mass spectroscopy (MH+) 438.

[2294] Anal. Calcd for C₂₅H₃₁N₃O₄; C, 68.63 H, 7.14 N, 9.60. Found: C,68.71 H, 6.99, N, 9.42.

Example 7-20 Synthesis of 5-(S)-[N′-((S orR)-2-Hydroxy-3,3-dimethylbutyryl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-oneand 5-(S)-[N′-((S orR)-2-Hydroxy-3,3-dimethylbutyryl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2295] Following General Procedure D above using2-hydroxy-3,3-dimethylbutyric acid (Aldrich) and5-(S)-[L-valinyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-C), the title compound was prepared as acolorless solid. The diastereomers were purified by flash chromatographyusing 99:1 CHCl₃/MeOH.

[2296] Isomer 1:

[2297] NMR data was as follows:

[2298]¹H-nmr (CDCl₃): δ=7.60-7.28 (m, 8H), 6.63 (d, 1H), 5.26 (d, 1H),4.53 (m, 1H), 3.74 (s, 1H), 3.35 (s, 3H), 2.12 (m, 1H), 0.998 (m, 15H).

[2299] C₂₆H₃₃N₃O₄ (MW=451); mass spectroscopy (MH+) 452.

[2300] Anal. Calcd for C₂₆H₃₃N₃O₄.0.5 mol H₂O; C, 67.80 H, 7.16 N, 9.11.Found: C, 68.32 H, 7.06 N, 8.91.

[2301] Isomer 2:

[2302] NMR data was as follows:

[2303]¹H-nmr (CDCl₃): δ=7.59-7.28 (m, 8H), 6.82 (d, 1H), 5.25 (d, 1H),4.52(m, 1H), 3.74 (s, 1H), 3.33 (s, 3H), 2.16 (m, 1H), 0.997 (m, 15H).

[2304] C₂₆H₃₃N₃O₄ (MW=451); mass spectroscopy (MH+) 452

[2305] Anal. Calcd for C₂₆H₃₃N₃O₄; C, 69.16 H, 7.37 N, 9.31. Found: C,69.33 H, 7.49 N, 9.22.

Example 7-22 Synthesis of5-{N′-(4-Phenyl-furazan-3-yl)alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2306] Following General Procedure D and usingN-(4-phenyl-furazan-3-yl)alanine (Example I) and5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-A),the title compound was prepared. The reaction was monitored by tlc(Rf=0.75, 5% MeOH/CHCl₃) and product was purified by chromatography(silica, CHCl₃).

[2307] NMR data was as follows:

[2308]¹H-nmr (CDCl₃): δ=4.52 (m, 1H); 4.87 (t, 1H).

[2309] MW=453.50; mass spectroscopy (M+) 454.

Example 7-23 Synthesis of5-{N′-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dibenz[b,d]azepin-6-one

[2310] Following Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and5-amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d]azepin-6-one(Example 7-Z), the title compound was prepared. The reaction wasmonitored by tlc (Rf=0.3, 4% MeOH/CHCl₃) and product was purified bychromatography (silica, 4% MeOH/CHCl₃).

[2311] NMR data was as follows:

[2312]¹H-nmr (CDCl₃): δ=3.54 (s, 2H); 1.36 (m, 3H).

[2313] MW=475.58; mass spectroscopy (MH+) 476.

Example 7-24 Synthesis of5-{N′-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2314] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example7-K), the title compound was prepared. The reaction was monitored by tlc(Rf=0.35, 3% MeOH/CHCl₃) and product was purified by chromatography(silica, 3% MeOH/CHCl₃).

[2315] NMR data was as follows:

[2316]¹H-nmr (CDCl₃): δ=4.68 (m, 1H); 6.32 (dd, 1H). MW=581.66; massspectroscopy (M+) 582.

Example 7-25 Synthesis of5-{N′-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2317] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and5-amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-L), the title compound was prepared. The reaction wasmonitored by tlc (Rf=0.30, 5% MeOH/CHCl₃) and product was purified bychromatography (silica, 3% MeOH/CHCl₃).

[2318] NMR data was as follows:

[2319]¹H-nmr (CDCl₃): δ=4.07 (m, 1H); 4.70 (m, 1H); 5.24 (d, 1H).

[2320] MW=503.55; mass spectroscopy (M+) 504.

Example 7-26 Synthesis of5-{N′-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-(2′,2′,2′-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2321] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and5-amino-7-(2′,2′,2′-trifluoroethyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one(Example 7-M), the title compound was prepared. The reaction wasmonitored by tlc (Rf=0.15, 5% MeOH/CHCl₃) and product was purified bychromatography (silica, 5% MeOH/CHCl₃).

[2322] NMR data was as follows:

[2323]¹H-nmr (CDCl₃): δ=4.07 (m, 1H); 4.69 (m, 1H); 5.02 (m, 1H); 5.37(d, 1H).

[2324] MW=531.48; mass spectroscopy (MH+) 530.

Example 7-27 Synthesis of5-{N′-(3,5-Difluorophenylacetyl)-L-alaninyl}amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2325] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and5-amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example7-N), the title compound was prepared. The reaction was monitored by tlc(Rf=0.35, 5% MeOH/CHCl₃) and product was purified by chromatography(silica, 5% MeOH/CHCl₃).

[2326] NMR data was as follows:

[2327]¹H-nmr (CDCl₃): δ=1.43 (dd, 3H); 3.94 (m, 1H); 4.68 (m, 1H); 5.18(d, 1H).

[2328] MW=531.60); mass spectroscopy (M+) 533.

Example 7-28 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2329] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-alaninyl)-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-O), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.4, 10% MeOH/CHCl₃) and product waspurified by chromatography (silica, 2.5% MeOH/CHCl₃).

[2330] NMR data was as follows:

[2331]¹H-nmr (CDCl₃): δ=3.36 (s, 3H); 4.67 (m, 1H); 5.05 (s, 1H); 5.21(m, 1H).

[2332] MW=497.47; mass spectroscopy (M+) 498.

Example 7-29 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-alaninyl}-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2333] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-alaninyl)-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-P), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.4, 10% MeOH/CHCl₃) and product waspurified by 2.5% chromatography (silica, MeOH/CHCl₃).

[2334] NMR data was as follows:

[2335]¹H-nmr (CDCl₃): δ=1.45 (dd, 3H); 3.31 (d, 3H).

[2336] MW=497.47; mass spectroscopy (MH+) 498.

Example 7-30 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2337] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-alaninyl)-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-Q), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.4, 10% MeOH/CHCl₃) and product waspurified by chromatography (silica, 2.5% MeOH/CHCl₃).

[2338] NMR data was as follows:

[2339]¹H-nmr (CDCl₃): δ=1.44 (dd, 3H); 3.35 (d, 3H).

[2340] MW=497.47; mass spectroscopy (M+) 498.

Example 7-31 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2341] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-alaninyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-R), the title compound was prepared. Theproduct was purified by chromatography (silica, 2.5% MeOH/CHCl₃).

[2342] NMR data was as follows:

[2343]¹H-nmr (CDCl₃): δ=1.48 (dd, 3H); 3.45 (m, 1H).

[2344] MW=519.55; mass spectroscopy (M+) 520.

Example 7-32 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-alaninyl}amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2345] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-alaninyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-S), the title compound was prepared. Theproduct was purified by chromatography (silica, 1-2% MeOH/CHCl₃).

[2346] NMR data was as follows:

[2347]¹H-nmr (CDCl₃): δ=1.48 (dd, 3H); 5.04 (d, 1H).

[2348] MW=597.66; mass spectroscopy (M+) 599.

Example 7-33 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2349] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-valinyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-T), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.3, 2.5% MeOH/CHCl₃) and product waspurified by chromatography (silica, 2.5% MeOH/CHCl₃).

[2350] NMR data was as follows:

[2351]¹H-nmr (CDCl₃): δ=3.42 (m, 1H); 4.07 (m, 1H); 5.03 (d, 1H).

Example 7-34 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2352] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-valinyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-U), the title compound was prepared. Theproduct was purified by chromatography (silica, 1-2% MeOH/CHCl₃).

[2353] NMR data was as follows:

[2354]¹H-nmr (CDCl₃): δ=3.54 (m, 1H); 4.35 (m, 1H); 5.03 (d, 1H).

[2355] MW=625.71; mass spectroscopy (M+) 625.

Example 7-35 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2356] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-valinyl)-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-V), the title compound was prepared. Theproduct was purified by chromatography (silica, 5% MeOH/CHCl₃).

[2357] NMR data was as follows:

[2358]¹H-nmr (DMSO-d₆): δ=4.25 (m, 1H); 4.52 (m, 1H); 5.05 (t, 1H); 5.24(2 doublets, 1H).

[2359] MW=577.67; mass spectroscopy (M+) 578.

Example 7-36 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2360] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-valinyl)-amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-W), the title compound was prepared. Theproduct was purified by chromatography (silica, 2.5% MeOH/CHCl₃).

[2361] Anal. Calc.: C, 71.02; H, 5.96; N, 6.72. Found: C, 71.10, H,6.12, N, 6.63.

Example 7-37 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2362] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-valinyl)-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-X), the title compound was prepared. Theproduct was purified by chromatography (silica, 2.5% MeOH/CHCl₃).

[2363] Anal. Calc.: C, 71.02; H, 5.96; N, 6.72. Found: C, 71.10, H,6.12, N, 6.63.

Example 7-38 Synthesis of5-{N′-[(S)-3,5-Difluoromandelyl]-L-valinyl}amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one

[2364] Following General Procedure D and using (S)-3,5-difluoromandelicacid (Example L) and5-(L-valinyl)-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-onehydrochloride (Example 7-Y), the title compound was prepared. Theproduct was purified by chromatography (silica, 2.5% MeOH/CHCl₃).

[2365] Anal. Calc.: C, 71.02; H, 5.96; N, 6.72. Found: C, 71.10, H,6.12, N, 6.63.

[2366] 8. Benzodiazepine Derivatives and Related Compounds

General Procedure 8-A N-1-Methylation of Benzodiazepines

[2367] A solution of benzodiazepine (1 eq.) in DMF (0.1 M concentration)at 0° C. was treated with potassium tert-butoxide (1.0 eq., 1.0 Msolution in THF). After stirring for 30 minutes at 0° C., iodomethane(1.3 eq.) was added and stirring continued for 25 minutes. The mixturewas diluted with methylene chloride and washed with water and brine. Theorganic phase was dried over Na₂SO₄, filtered, and concentrated. Thecrude product was then either purified by trituration with 1:1ether/hexanes or chromatographed via HPLC using ethyl acetate/hexanes asthe eluent.

General Procedure 8-B Cbz Removal Procedure

[2368] A flask was charged with the Cbz-protected 3-aminobenzodiazepine(1 eq.). To this was added HBr (34 eq.; 30% solution in acetic acid).Within 20 minutes all of the starting material dissolves. The reactionwas stirred for 5 hours at ambient temperature. Ether was added to theorange solution causing the HBr.amine salt to precipitate. The mixturewas decanted. This process of adding ether and decanting was repeatedthrice in an effort to remove acetic acid and benzyl bromide. Toluenewas added and the mixture concentrated in vacuo. This step was alsorepeated. The HBr salt was partitioned between ethyl acetate and 1 MK₂CO₃. The aqueous layer was back-extracted with ethyl acetate. Thecombined organics were washed with brine, dried over Na₂SO₄, filtered,and concentrated.

General Procedure 8-C Boc Removal Procedure

[2369] A solution of Boc-protected amine (1 eq.) in methylene chloride(0.15 M concentration) was cooled to 0° C. and treated withtrifluoroacetic acid (30 eq.). After 10 minutes at 0° C., the coolingbath was removed and stirring continued at ambient for 20 minutes to 1hour. The mixture was concentrated in vacuo to remove excesstrifluoroacetic acid. The residue was dissolved in methylene chlorideand washed with saturated aqueous NaHCO₃ or 1 M K₂CO₃ and brine. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated.

General Procedure 8-D Azide Transfer Reaction Using KHMDS

[2370] The azido derivative was prepared using the procedure describedin John W. Butcher et al., Tet. Lett., 37, 6685-6688 (1996).

General Procedure 8-E Azide Transfer Reaction Using LDA

[2371] To a solution of diisopropylamine (1.1 eq.) in 1 mL of dry THFcooled to −78° C. was added n-butyl lithium (1.6M in hexane) (1.1 eq.)dropwise maintaining the reaction temperature at −78° C. The reactionmixture was stirred for 30 min. at −78° C. and then the lactam (0.471mM) was added dropwise as a solution in 1 mL of dry THF. The reactionmixture was stirred at −78° C. for 30 min. and then a pre-cooledsolution of trisyl azide (1.2 eq.) was added as a solution in 1 mL ofdry THF. The reaction mixture was stirred at −78° C. for 20 min. andthen quenched with acetic acid (4.0 eq.). The reaction mixture was thenstirred at 40° C. for 2 hrs. The reaction was then poured into EtOAc andwashed with water, sodium bicarbonate and brine, and then dried oversodium sulfate, filtered and concentrated. The residue was purified byLC 2000 chromatography.

General Procedure 8-F Azido Group Reduction

[2372] The azido group was reduced to the corresponding primary amineusing the procedure described in John W. Butcher et al., Tet. Lett., 37,6685-6688 (1996).

General Procedure 8-G N-Alkylation of Amides or Lactams Using SodiumHydride or Potassium tert-Butoxide

[2373] To a slurry of sodium hydride or potassium tert-butoxide (1.1 eq)in 15 mL of dry DMF was added the appropriate amide (0.0042 moles) as asolution in 10 mL of DMF. The alkyl iodide was then added and a thickslurry resulted. The reaction became less thick as time elapsed and whencomplete by TLC the reaction had become homogeneous. The reactionmixture was poured over ice and extracted into ethyl acetate. Theorganic layer was washed with water, followed by brine. The organiclayer was then dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by HPLC (LC 2000),eluting with an ethyl acetate/hexane system.

General Procedure 8-H N-Alkylation of Amides or Lactams Using KHMDS

[2374] To the appropriate amide or lactam in THF cooled to −78° C. wasadded KHMDS dropwise and the reaction mixture was stirred for 30 min. at−78° C. The alkyl iodide was then added dropwise while maintaining thetemperature at −70° C. The cooling bath was then removed and reactionwas allowed to warm to room temperature and stirring was continued for 2hours. The reaction mixture was then poured over ice and extracted intoethyl acetate. The organic extracts were washed with water, followed bybrine. The organic layer was then dried over sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified byHPLC (LC 2000), eluting with an ethyl acetate/hexane system.

General Procedure 8-I N-Alkylation of Amides or Lactams Using CesiumCarbonate

[2375] To a solution of the amide or lactam in DMF was added cesiumcarbonate (1.05 eq) and an alkyl iodide (1.1 eq). The mixture wasallowed to stir overnight at room temperature and then the reactionmixture was dilluted with ethyl acetate and washed with water, followedby brine. The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by HPLC(LC 2000), eluting with an ethyl acetate/hexane system.

General Procedure 8-J BOC Removal Procedure

[2376] To an N-Boc protected compound was added CH₂Cl₂/TFA (4:1) at roomtemperature. The reaction mixture was stirred at room temperature for 3hours and then concentrated. The residue was extracted intodichloromethane and washed with water, saturated sodium bicarbonate,dried over Na₂SO₄, filtered and concentrated to give the free amine.

General Procedure 8-K Azide Transfer Procedure

[2377] This azide transfer procedure is a modification of the proceduredescribed in Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L.J. Am. Chem. Soc. 1990, 112, 4011-4030. To a solution of the lactamsubstrate (1.0 eq.) in THF (˜0.1 M) under N₂ at −78° C. was added asolution of KN(TMS)₂ (1.1 eq. of 0.5 M in Toluene, Aldrich) dropwiseover a period of 2-10 minutes. A slight exotherm was often observed byan internal thermometer, and the resulting solution was stirred for 5-15minutes, while re-cooling to −78° C. Then, trisyl azide (1.1-1.5 eq.,CAS No. 36982-84-0, prepared as described by references in the Evansreference above) in THF (˜-0.5 M), either precooled to −78° C. or atroom temperature, was added via cannula over a period of 0.5-5 minutes.Again, a slight exotherm was generally noted. The resulting solution wasstirred for from 5-10 minutes, while re-cooling to −78° C. Then, AcOH(4.5-4.6 eq., glacial) was added, the cooling bath removed and themixture allowed to warm to room temperature with stirring for 12-16hours. The mixture was diluted with EtOAc, in a 2-5 volume multiple ofthe initial THF volume, and washed with dilute aq. NaHCO₃ (1-2×),0.1-1.0 M aq. HCl (0-2×), and brine (1×). The organic phase was thendried over MgSO₄, filtered, concentrated to provide the crude product.

General Procedure 8-L Azide Reduction to an Amine

[2378] A mixture of the azide in absolute EtOH (0.03-0.07 M) and 10%Pd/C (˜⅓ by weight of the azide) was shaken in a Parr apparatus under H₂(35-45 psi) at room temperature for 3-6 hours. The catalyst was removedby filtration through a plug of Celite, rinsing with absolute EtOH, andthe filtrate concentrated to provide the crude amine product.

General Procedure 8-M Amide Alkylation Using Cesium Carbonate

[2379] This procedure is a modification of the procedure described inClaremon, D. A.; et al, PCT Application: WO 96-US8400 960603. To amixture of 2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No.49799-48-6) in DMF (1.0 eq., 0.7 M) under N₂ at room temperature wasadded Cs₂CO₃ (2.2 eq.) and the appropriate alkyl halide (2.2 eq.). Themixture was stirred at room temperature for 5.5-16 hours. The mixturewas partitioned between EtOAc and sat. NaHCO₃. The aqueous layer wasextracted with EtOAc (1-2×) and the combined EtOAc extracts were driedover Na₂SO₄, filtered, and concentrated to provide the crude product.

General Procedure 8-N BOC Removal Procedure

[2380] A stream of anhydrous HCl gas was passed through a stirredsolution of the N-t-Boc protected amino acid in 1,4-dioxane (0.03-0.09M), chilled in a ice bath to ˜10° C. under N₂, for 10-15 minutes. Thesolution was capped, the cooling bath removed, and the solution wasallowed to warm to room temperature with stirring for 2-8 hours,monitoring by TLC for the consumption of starting material. The solutionwas concentrated (and in some instances dissolved in CH₂Cl₂ thenre-concentrated and placed in vacuum oven at 60-70° C. to remove most ofthe residual dioxane) and used without further purification.

Example 8-A Synthesis of3-Amino-1,3-dihydro-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2-one StepA—Preparation of1.2-Dihydro-3H-1-methyl-5-(1-piperidinyl)-1.4-benzodiazepin-2-one

[2381] A solution of phosphorous pentachloride (1.2 eq) in methylenechloride was added dropwise to a solution of1-methyl-1,2,3,4-tetrahydro-3H-1,4-benzodiazepin-2,5-dione (Showell, G.A.; Bourrain, S.; Neduvelil, J. G.; Fletcher, S. R.; Baker, R.; Watt, A.P.; Fletcher, A. E.; Freedman, S. B.; Kemp, J. A.; Marshall, G. R.;Patel, S.; Smith, A. J.; Matassa, V. G. J. Med. Chem. 1994, 37, 719.) inmethylene chloride. The resultant yellowish-orange solution was stirredat ambient temperature for 2.5 hours; the solvent was removed in vacuo.The orange residue was redissolved in methylene chloride, cooled to 0°C., and treated with a solution of piperidine (2 eq) and triethylamine(2 eq) in methylene chloride. The cooling bath was removed and thereaction stirred for 18 hours. The reaction mixture was washed withsaturated aqueous NaHCO₃ (back-extracted with methylene chloride) andbrine. The organic phase was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified via HPLC eluting with a gradientof 4 to 10% methanol/methylene chloride affording the title intermediateas a yellow solid having a melting point of 103-105° C.

[2382] C₁₅H₁₉N₃O (MW 257.37); mass spectroscopy 257.

[2383] Anal. Calcd for C₁₅H₁₉N₃O: C, 70.01; H, 7.44; N, 16.33. Found: C,69.94; H, 7.58; N, 16.23.

Step B—Preparation of1,2-Dihydro-3H-1-methyl-3-oximido-5-(1-piperidinyl)-1 4-benzodiazepin-2-one

[2384] Potassium tert-butoxide (2.5 eq) was added in two portions to a−20° C. solution of1,2-dihydro-3H-1-methyl-5-(1-piperidinyl)-1,4-benzodiazepin-2-one (1 eq)in toluene). After stirring at −20° C. for 20 min, isoamyl nitrite (1.2eq.; Aldrich) was added to the red reaction mixture. The reaction wasstirred at −20 ° C. for 5 hours at which time the reaction was done byTLC. The cooling bath was removed and the reaction quenched with 0.5 Mcitric acid. After stirring for 10 minutes, diethyl ether was added. Thesuspension was stirred at ambient temperature overnight then filteredwashing with ether. The resultant cream colored solid had a meltingpoint of 197-200° C.

[2385]¹H NMR data of the E/Z isomers was as follows:

[2386]¹H NMR (300 MHz, CDCl₃): δ=7.64 (1H, bs), 7.48 (2H, d, J=7.4 Hz),7.35-7.20 (6H, m), 6.75 (1H, bs), 3.8-3.2 (8H, m), 3.46 (3H, s), 3.42(3H, s) 1.90-1.40 (12H, m).

[2387] C₁₅H₁₈N₄O₂ (MW=286.37); mass spectroscopy 286.

Step C—Preparation of1,2-dihydro-3H-1-methyl-3-[O-(ethylaminocarbonyl)oximidol-5-(1-piperidinyl)-1,4-benzodiazepin-2-one

[2388] A mixture of1,2-dihydro-3H-1-methyl-3-oximido-5-(1-piperidinyl)-1,4-benzodiazepin-2-one(1 eq) in THF was treated with ethyl isocyanate (1.7 eq) andtriethylamine (0.6 eq). The mixture was heated to 64° C. for 4 hours.The mixture was concentrated and the residue purified, by HPLC elutingwith 5% methanol/methylene chloride.

[2389]¹H NMR data of the E/Z isomers was as follows:

[2390]¹H NMR (300 MHz, CDCl₃): δ=7.50 (2H, dd, J=8.4, 1.5 Hz), 7.35-7.22(6H, m), 6.42 (1H, bt), 6.20 (1H, bt), 3.7-3.4 (8H, m), 3.46 (3H, s),3.44 (3H), s), 3.25 (4H, m), 1.9-1.4 (12H, m), 1.12 (3H, t, J=6.3 Hz),1.10 (3H, t, J=6.3 Hz).

[2391] C₁₈H₂₃N₅O₃ (MW=357.46); mass spectroscopy 357.

Step D—Preparation of3-Amino-1,3-dihydro-2H-1-methyl-5-(1-piperidinyl)-1.4-benzodiazepin-2-one

[2392] The1,2-dihydro-3H-1-methyl-3-[O-(ethylaminocarbonyl)oximido]-5-(1-piperidinyl)-1,4-benzodiazepin-2-one(1 eq) was hydrogenated in methanol over 5% palladium on carbon (0.15eq) at 43 psi for 3.25 hours. The reaction was filtered through celiteand concentrated in vacuo. The residue was taken up in methylenechloride and filtered a second time through celite. The filtrate wasconcentrated and the resultant foam was used immediately.

Example 8-B Synthesis of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-oneStep A—Preparation of(S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate

[2393] The title intermediate was prepared according to Reider, P. J.;Davis, P.; Hughes, D. L.; Grabowski, E. J. J. J. Org. Chem. 1987, 52,955 using3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (BockM. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber, D. F.;Freidinger, R. M.; Hirshfield, J.; Springer, J. P. J. Org. Chem. 1987,52, 3232.) as the starting material.

Step B—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-2.3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2394](S)-3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate was freebased by partitioning between methylene chloride and 1M potassiumcarbonate. The free amine was then coupled with N-Boc-alanine followingGeneral Procedure D.

[2395] C₂₄H₂₈N₄O₄ (MW=436.56); mass spectroscopy 436.

[2396] Anal. Calc. for C₂₄H₂₈N₄O₄: C, 66.03; H, 6.47; N, 12.84. Found:C, 65.79; H, 6.68; N, 12.80.

[2397] Step C—Preparation of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2398] Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title compound was prepared as a white foam.

[2399] Anal. Calc. for C₁₉H₁₉N₄O₂: C, 69.21; H, 6.64; N, 15.37. Found:C, 70.11; H, 6.85; N, 15.01.

Example 8-C Synthesis of3-(L-Alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-oneStep A—Preparation of3-(Benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2400] A solution of3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-phenyl-1H-1,4-Benzodiazepin-2-one(1 eq; Neosystem) in DMF was cooled to 0° C. and treated with potassiumtert-butoxide (1 eq; 1.0M solution in THF). The resultant yellowsolution was stirred at 0° C. for 30 minutes then quenched with methyliodide (1.3 eq). After stirring an addition 25 minutes the reaction wasdiluted with methylene chloride and washed with water and brine. Theorganic phase was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified via HPLC chromatography eluting with a gradient of20→30% ethyl acetate/hexanes.

[2401] C₂₄H₂₀ClN₃O₃ (MW=433.92); mass spectroscopy 433.

[2402] Anal. calcd for C₂₄H₂₀ClN₃O₃: C, 66.44; H, 4.65; N, 9.68. Found:C, 66.16; H, 4.50; N, 9.46.

Step B—Preparation of3-Amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

[2403] Following General Procedure 8-B using3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam which was usedimmediately in Step C.

Step C—Preparation of3-[N′-tert-Butylcarbamate)-L-alaninyl]-amino-7-chloro-1.3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

[2404] Following General Procedure D using N-Boc-L-alanine and3-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

[2405] C₂₄H₂₈ClN₄O₄ (MW=471.18); mass spectroscopy 471

[2406] Anal. calcd for C₂₄H₂₈ClN₄O₄: C, 61.21; H, 5.78; N, 11.90. Found:C, 61.24; H, 5.59; N, 11.67.

Step D—Preparation of3-(L-Alaninyl)amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one

[2407] Following General Procedure 8-C using3-[N′-tert-butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

Example 8-D Synthesis of3-(L-Alaninyl)amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-oneStep A—Preparation of3-(Benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2408] Following General Procedure 8-A using3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one(Neosystem), the title intermediate was prepared as a white foam.

[2409] C₂₄H,₉BrFN₃O₃ (MW=496.36); mass spectroscopy 497.

[2410] Anal. calcd for C₂₄H₁₉BrFN₃O₃: C, 58.08; H, 3.86; N, 8.47. Found:C, 57.90; H, 4.15; N, 8.20.

Step B—Preparation of3-Amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

[2411] Following General Procedure 8-B using3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam which was usedimmediately in Step C.

Step C—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-7-bromo-1.3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

[2412] Following General Procedure D using N-Boc-L-alanine (Novo) and3-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

[2413] C₂₄H₂₆BrFN₄O₄ (MW=533.12); mass spectroscopy 533.2.

[2414] Anal. calcd for C₂₄H₂₆BrFN₄O₄: C, 54.04; H, 4.91; N, 10.50.Found: C, 53.75; H, 4.92; N, 10.41.

Step D—Preparation of3-(L-Alaninyl)-amino-7-bromo-13-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1.4-benzodiazepin-2-one

[2415] Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

Example 8-E Synthesis of3-(N′-Methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-oneStep A—Preparation of3-[N′-(tert-Butylcarbamate)-N′-methyl-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2416] Following General Procedure D and using(S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(Example 8-B) and N-tert-Boc-N-methyl-alanine (Sigma), the titleintermediate was obtained as a white solid.

[2417] C₂₅H₃₀N₄O₄ (MW=450.2); mass spectroscopy (M+1) 451.2.

[2418] Anal. calcd for C₂₅H₃₀N₄O₄: C, 66.65; H, 6.71; N, 12.44. Found:C, 66.66; H, 6.89; N, 12.21.

Step A—Preparation of3-(N′-Methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2419] Following General Procedure 8-C and using3-[N′-(tert-butylcarbamate)-N′-methyl-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

[2420] C₂₀H₂₂N₄O₂ (MW=350.46); mass spectroscopy (M+1) 351.4.

[2421] Anal. calcd for C₂₀H₂₂N₄O₂: C, 68.55; H, 6.33; N, 15.99. Found,C, 68.36; H, 6.20; N, 15.79.

Example 8-F Synthesis of3-(L-Alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-oneStep A—Preparation of3-(Benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazeipin-2-one

[2422] Following General Procedure 8-A using3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one(Neosystem), the title intermediate was prepared as a white solid havinga melting point of 232-233° C.

[2423] C₂₄H₁₉Cl₂N₃O₃ (MW=468.36); mass spectroscopy 468.

[2424]¹H NMR (300 MHz, CDCl₃): δ=7.67 (1H, m), 7.52 (1H, dd, J=2.4, 8.7Hz), 7.42-7.26 (9H, m), 7.07 (1H, d, J=2.4 Hz), 6.70 (1H, d, J=8.3 Hz),5.35 (1H, d, J=8.4 Hz), 5.14 (2H, ABq, J=19.6 Hz), 3.47 (3H, s).

[2425]¹³C NMR (75 MHz, CDCl₃): δ=166.66, 165.65, 155.72, 140.52, 136.99,136.0, 132.87, 131.99, 131.47, 131.40, 131.38, 131.16, 130.54, 130.06,128.45, 128.08, 128.03, 127.72, 127.22, 123.28, 122.01, 68.95, 67.02,35.32.

Step B—Preparation of3-Amino-7-chloro-1.3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one

[2426] Following General Procedure 8-B using3-(benzyloxycarbonyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam which was usedimmediately in Step C.

Step C—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one

[2427] Following General Procedure D using N-Boc-L-alanine and3-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

[2428] C₂₄H₂₆Cl₂N₄O₄ (MW=505.44); mass spectroscopy 505.2.

Step D—Preparation of3-(L-Alaninyl)-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one

[2429] Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-7-chloro-1,3-dihydro-1-methyl-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

Example 8-G Synthesis of3-(L-Alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-Benzodiazepin-2-oneStep A—Preparation of3-(Benzyloxycarbonyl)-amino-5-cylclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[2430] Following General Procedure 8-A using3-(benzyloxycarbonyl)-amino-5-cyclohexyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one(Neosystem), the title intermediate was prepared as a white solid havinga melting point of 205-206° C.

[2431] C₂₄H₂₇N₃O₃ (MW=405.54); mass spectroscopy 405.

[2432]¹H NMR (300 MHz, CDCl₃): δ=7.54 (1H, d, J=7.9 Hz), 7.48 (1H, d,J=7.7 Hz), 7.36-7.26 (7H, m), 6.54 (1H, d, J=8.3 Hz), 5.15 (1H, d, J=8.0Hz), 5.09 (2H, ABq, J=17.1 Hz), 3.39 (3H, s), 2.77 (1H, m), 2.01 (1H,bd, J=13.6 Hz), 1.85 (1H, bd, J=12.4 Hz), 1.68-1.49 (4H, m), 1.34-1.02(4H, m).

Step B—Preparation of3-Amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

[2433] Following General Procedure 8-B using3-(benzyloxycarbonyl)-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam which was usedimmediately in Step C.

[2434] C₁₆H₂₁N₃O (MW+H=272.1763); mass spectroscopy 272.1766

Step C—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

[2435] Following General Procedure D using N-Boc-L-alanine and3-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam.

[2436] C₂₄H₃₄N₄O₄ (MW=442.62); mass spectroscopy (M+H) 443.2.

Step D—Preparation of3-(L-Alaninyl)amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

[2437] Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

[2438] C₁₉H₂₆N₄O₂ (M+H=343.2136); mass spectroscopy found 343.2139.

Example 8-H Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-oneStep A—Preparation of2-[N-(α-Isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone

[2439] A solution of α-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1eq; prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975,31, 863.) in dry THF was cooled to 0° C. and treated with oxalylchloride (1 eq.) and 3 drops of DMF. After stirring for 15 minutes at 0°C., the cooling bath was removed and stirring continued at ambienttemperature for 40 minutes. The solution was recooled to 0° C. Asolution of 2-amino-5-nitrobenzophenone (0.9 eq.; Acros) and4-methylmorpholine (2.0 eq.) in dry THF was added via cannulation to theacid chloride. The cooling bath was removed and the reaction stirred atambient for 5 hours. The reaction was diluted with methylene chlorideand washed with 0.5 M citric acid, saturated aqueous NaHCO₃, and brine.The organic phase was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified via preparative LC2000 eluting with a gradient of15→20% ethyl acetate/hexanes giving an off-white foam.

[2440] C₂₆H₂₅N₃O₆S (MW=507.61); mass spectroscopy found 507.9.

[2441] Anal. calcd for C₂₆H₂₅N₃O₆S: C, 61.53; H, 4.96; N, 8.28. Found:C, 61.70; H, 4.99; N, 8.22.

Step B—Preparation of2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone

[2442] Ammonia gas was bubbled into a solution2-[N-(α-isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone(1 eq) in THF at 0° C. After 35 minutes mercury(II) chloride (1.1 eq)was added. The ice bath was removed and ammonia gas was continued tobubble through the suspension for 4 hours. The bubbler was removed andthe reaction continued to stir for 16 hours. The mixture was filteredthrough celite washing with THF. The filtrate was concentrated in vacuo.The crude solid was used in step C without further purification.

Step C—Preparation of3-(Benzyloxycarbonyl)-amino-2,3-dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

[2443]2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-5-nitrobenzophenone(1 eq) was treated with glacial acetic acid and ammonium acetate (4.7eq). The suspension was stirred at ambient temperature for 21 hours.After concentrating the reaction in vacuo, the residue was partitionedbetween ethyl acetate and 1 N NaOH. The aqueous layer was back-extractedwith ethyl acetate. The combined organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified viaflash chromatography eluting with a gradient of 2→3% isopropylalcohol/methylene chloride.

[2444] C₂₃H₁₈N₄O₅ (MW=430.45); mass spectroscopy found (M+H) 431.2.

[2445] Anal. calcd for C₂₃H₁₈N₄O₅: C, 64.18; H, 4.22; N, 13.02. Found:C, 64.39; H, 4.30; N, 13.07.

Step D—Preparation of3-(Benzyloxycarbonyl)-amino-2.3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

[2446] Following General Procedure 8-A and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam.

[2447] C₂₄H₂₀N₄O₅ (MW=444.48); mass spectroscopy found (M+H) 445.2.

[2448] Anal. calcd for C₂₄H₂₀N₄O₅: C, 64.86; H, 4.54; N, 12.60. Found:C, 65.07; H, 4.55; N, 12.46.

Step E—Preparation of3-Amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one

[2449] Following General Procedure 8-B and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam which was usedimmediately in Step F.

Step F—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-2.3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

[2450] Following General Procedure D using N-Boc-L-alanine and3-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow solid.

[2451] C₂₄H₂₇N₅O₆ (MW=481.56); mass spectroscopy found (M+H) 482.3.

[2452] Anal. calcd for C₂₄H₂₇N₅O₆: C, 59.88; H, 5.61; N, 14.55. Found:C, 60.22; H, 5.75; N, 13.91.

Step G—Preparation of3-(L-Alaninyl)-amino-2.3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

[2453] Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam. The crude materialwas used immediately.

Example 8-I Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-oneStep A—Preparation of3-Amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

[2454] A flask was charged with3-(benzyloxycarbonyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one(1 eq.; Example 8-D, Step A) and 10% palladium on carbon. Methanol wasadded, and the flask was placed under a balloon of H₂. The reaction wasstirred for 21 hours. The mixture was filtered through celite washingwith methanol. The filtrate was concentrated to a white solid.

[2455] C₁₆H₁₄FN₃O (MW=283.33); mass spectroscopy found (M+H) 284.1.

Step B—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

[2456] Following General Procedure D using N-Boc-L-alanine and3-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white solid.

[2457] C₂₄H₂₇FN₄O₄ (MW=454.50); mass spectroscopy found (M+H) 455.4.

[2458] Anal. calcd for C₂₄H₂₇FN₄O₄: C, 63.44; H, 5.95; N, 12.33. Found:C, 63.64; H, 6.08; N, 12.16.

Step C—Preparation of3-(L-Alaninyl)-amino-7-bromo-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one

[2459] Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a white foam. The crude materialwas used immediately.

Example 8-J Synthesis of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-oneStep A—Preparation of 2-Amino-3′-fluorobenzophenone

[2460] A solution of 3-bromofluorobenzene (1 eq.) in THF was cooled to−78° C. under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6M solution in pentane) at a rate of 40 ml/h. The internal temperaturedid not rise above −74° C. The orange solution was stirred at −78° C.for 30 minutes prior to the addition of anthranilonitrile (0.6 eq.) as asolution in THF. The reaction was warmed to 0° C. and stirred for 2hours. 3N HCl was added to the mixture and stirring continued for 30minutes. The reaction was diluted with ethyl acetate and the layers wereseparated. The aqueous layer was back-extracted thrice with ethylacetate. The combined extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified via HPLCeluting with 93:7 hexanes/ethyl acetate.

[2461] C₁₃H₁₀FNO (MW=215.24); mass spectroscopy found (M+H) 216.3.

[2462]¹H NMR (300 MHz, CDCl₃) d 7.44-7.19 (6H, m), 6.74 (1H, d, J=8.0Hz), 6.61 (1H, dd, J=0.94, 7.9 Hz), 6.10 (2H, bs).

Step B—Preparation of2-[N-(α-Isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-3′-fluorobenzophenone

[2463] A solution of α-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1eq; prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975,31, 863.) in dry THF was cooled to 0° C. and treated with oxalylchloride (1 eq.) and 3 drops of DMF. After stirring for 15 minutes at 0°C., the cooling bath was removed and stirring continued at ambienttemperature for 40 minutes. The solution was recooled to 0° C. Asolution of 2-amino-3′-fluorobenzophenone (0.9 eq.) and4-methylmorpholine (2.0 eq.) in dry THF was added via cannulation to theacid chloride. The cooling bath was removed and the reaction stirred atambient for 5 hours. The reaction was diluted with methylene chlorideand washed with 0.5 M citric acid, saturated aqueous NaHCO₃, and brine.The organic phase was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified via preparative LC2000 eluting with a gradient of15→20% ethyl acetate/hexanes giving an off-white foam.

[2464] C₂₆H₂₅N₂O₄S (MW=480.60); mass spectroscopy found (M+NH₄ ⁺) 498.3.

[2465]¹H NMR (300 MHz, CDCl₃) d 11.39 (1H, s), 8.59 (1H, d, J=6.0 Hz),7.63-7.55 (2H, m), 7.48-7.27 (9H, m), 7.14 (1H, dt, J=1.2, 8.4 Hz), 5.94(1H, d, J=7.2 Hz), 5.58 (1H, d, J=8.7 Hz), 5.17 (2H, ABq, J=14.7 Hz),3.25 (1H, sep, J=6.6 Hz), 1.44 (3H, d, J=6.0 Hz), 1.28 (3H, d, J=6.6Hz).

Step C—Preparation of2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-3′-fluorobenzophenone

[2466] Ammonia gas was bubbled into a solution2-[N-(α-isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-3′-fluorobenzophenone(1 eq) in THF at 0° C. After 35 minutes mercury(II) chloride (1.1 eq)was added. The ice bath was removed and ammonia gas was continued tobubble through the suspension for 4 hours. The bubbler was removed andthe reaction continued to stir for 16 hours. The mixture was filteredthrough celite washing with THF. The filtrate was concentrated in vacuo.The crude solid was used in step D without further purification.

Step D—Preparation of3-(Benzyloxycarbonyl)-amino-2,3-dihydro-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2467]2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-3′-fluorobenzophenone(1 eq) was treated with glacial acetic acid and ammonium acetate (4.7eq). The suspension was stirred at ambient temperature for 21 hours.After concentrating the reaction in vacuo, the residue was partitionedbetween ethyl acetate and 1 N NaOH. The aqueous layer was back-extractedwith ethyl acetate. The combined organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified viaflash chromatography eluting with a gradient of 2→3% isopropylalcohol/methylene chloride.

[2468] C₂₃H₁₈FN₃O₃ (MW=403.44); mass spectroscopy found (M+H) 404.4.

[2469] Anal. calcd for C₂₃H₁₈FN₃O₃.0.5H₂O: C, 66.98; H, 4.64; N, 10.18.Found: C, 67.20; H, 4.64; N, 9.77.

Step E—Preparation of3-(Benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2470] Following General Procedure 8-A and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam.

[2471] C₂₄H₂₀FN₃O₃ (MW=417.47); mass spectroscopy found (M+H) 418.3.

[2472] Anal. calcd for C₂₄H₂₀FN₃O₃: C, 69.06; H, 4.83; N, 10.07. Found:C, 69.33; H, 4.95; N, 9.82.

Step F—Preparation of3-Amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepin-2-one

[2473] Following General Procedure 8-B and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam which was usedimmediately in Step G.

Step G—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2474] Following General Procedure D using N-Boc-L-alanine and3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow solid.

[2475] C₂₄H₂₇FN₄O₄ (MW=454.50); mass spectroscopy found (M+H) 455.3.

[2476] Anal. calcd for C₂₄H₂₇FN₄O₄: C, 63.42; H, 5.99; N, 12.33. Found:C, 63.34; H, 6.01; N, 12.08.

Step H—Preparation of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2477] Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam. The crude materialwas used immediately.

Example 8-K Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-oneStep A—Preparation of 2-Amino-4′-fluorobenzophenone

[2478] A solution of 4-bromofluorobenzene (1 eq.) in THF was cooled to−78° C. under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6M solution in pentane) at a rate of 40 ml/h. The internal temperaturedid not rise above −74° C. The orange solution was stirred at −78° C.for 30 minutes prior to the addition of anthranilonitrile (0.6 eq.) as asolution in THF. The reaction was warmed to 0° C. and stirred for 2hours. 3N HCl was added to the mixture and stirring continued for 30minutes. The reaction was diluted with ethyl acetate and the layers wereseparated. The aqueous layer was back-extracted thrice with ethylacetate. The combined extracts were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The residue was purified via HPLCeluting with 93:7 hexanes/ethyl acetate.

[2479] C₁₃H₁₀FNO (MW=215.24); mass spectroscopy found (M+H) 216.3.

[2480] Anal. calcd for C₁₃H₁₀FNO: C, 72.55; H, 4.68; N, 6.51. Found: C,72.80; H, 4.51; N, 6.74.

Step B—Preparation of2-[N-(α-Isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-4′-fluorobenzophenone

[2481] A solution of α-(isopropylthio)-N-(benzyloxycarbonyl)glycine (1eq; prepared according to Zoller, V.; Ben-Ishai, D. Tetrahedron 1975,31, 863.) in dry THF was cooled to 0° C. and treated with oxalylchloride (1 eq.) and 3 drops of DMF. After stirring for 15 minutes at 0°C., the cooling bath was removed and stirring continued at ambienttemperature for 40 minutes. The solution was recooled to 0° C. Asolution of 2-amino-4′-fluorobenzophenone (0.9 eq.) and4-methylmorpholine (2.0 eq.) in dry THF was added via cannulation to theacid chloride. The cooling bath was removed and the reaction stirred atambient for 5 hours. The reaction was diluted with methylene chlorideand washed with 0.5 M citric acid, saturated aqueous NaHCO₃, and brine.The organic phase was dried over Na2SO4, filtered, and concentrated. Theresidue was purified via preparative LC2000 eluting with a gradient of15→20% ethyl acetate/hexanes giving an off-white foam.

[2482] C₂₆H₂₅N₂O₄S (MW=480.60); mass spectroscopy found (M+NH₄ ⁺) 498.2.

[2483]¹H NMR (300 MHz, CDCl₃) d 11.28 (1H, s), 8.56 (1H, d, J=8.4 Hz),7.78-7.73 (2H, m), 7.61-7.53 (2H, m), 7.36-7.32 (5H, m), 7.20-7.14 (3H,m), 5.98 (1H, d, J=7.5 Hz), 5.57 (1H, d, J=7.8 Hz), 5.16 (2H, ABq,J=14.7 Hz), 3.25 (1H, sep, J=6.0 Hz), 1.43 (3H, d, J=6.3 Hz), 1.27 (3H,d, J=6.6 Hz).

Step C—Preparation of2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-4′-fluorobenzophenone

[2484] Ammonia gas was bubbled into a solution2-[N-(α-isopropylthio)-N′-(benzyloxycarbonyl)-glycinyl]-amino-3′-fluorobenzophenone(1 eq) in THF at 0° C. After 35 minutes mercury(II) chloride (1.1 eq)was added. The ice bath was removed and ammonia gas was continued tobubble through the suspension for 4 hours. The bubbler was removed andthe reaction continued to stir for 16 hours. The mixture was filteredthrough celite washing with THF. The filtrate was concentrated in vacuo.The crude solid was used in step D without further purification.

[2485] Step D—Preparation of3-(Benzyloxycarbonyl)amino-2,3-dihydro-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one2-[N-(α-Amino)-N′-(benzyloxycarbonyl)-glycinyl]-amino-4′-fluorobenzophenone(1 eq) was treated with glacial acetic acid and ammonium acetate (4.7eq). The suspension was stirred at ambient temperature for 21 hours.After concentrating the reaction in vacuo, the residue was partitionedbetween ethyl acetate and 1 N NaOH. The aqueous layer was back-extractedwith ethyl acetate. The combined organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified viaflash chromatography eluting with a gradient of 2→3% isopropylalcohol/methylene chloride.

[2486] C₂₃H₁₈FN₃O₃ (MW=403.44); mass spectroscopy found (M+H) 404.4.

[2487] Anal. calcd for C₂₃H₁₈FN₃O₃.1.25H₂O: C, 64.85; H, 4.85. Found: C,64.80; H, 4.55.

[2488] Step E—Preparation of3-(Benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2489] Following General Procedure 8-A and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam.

[2490] C₂₄H₂₀FN₃O₃ (MW=417.47); mass spectroscopy found (M+H) 418.2.

[2491] Anal. calcd for C₂₄H₂₀FN₃O₃: C, 69.06; H, 4.83; N, 10.07. Found:C, 69.35; H, 4.93; N, 9.97.

Step F—Preparation of3-Amino-1,3-dihydro-1-methyl-5-(4-fluorophenyl)-2H-1,4-benzodiazepin-2-one

[2492] Following General Procedure 8-B and using3-(benzyloxycarbonyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam which was usedimmediately in Step G.

Step G—Preparation of3-[N′-(tert-Butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2493] Following General Procedure D using N-Boc-L-alanine and3-amino-1,3-dihydro-1-methyl-5-(3-fluorophenyl)-2H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow solid.

[2494] C₂₄H₂₇FN₄O₄ (MW=454.50); mass spectroscopy found (M+H) 455.4.

[2495] Anal. calcd for C₂₄H₂₇FN₄O₄.1.5H₂O: C, 59.86; H, 6.28; N, 11.64.Found: C, 60.04; H, 5.62; N, 11.27.

Step H—Preparation of3-(L-Alaninyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2496] Following General Procedure 8-C using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one,the title intermediate was prepared as a yellow foam. The crude materialwas used immediately.

Example 8-L Synthesis of3-(N′-L-Alaninyl)amino-2,3-dihydro-1-isobutyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2497] Step A: 1,3-Dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (preparedaccording to the procedure of M. G. Bock et al., J. Org. Chem. 1987, 52,3232-3239) was alkylated with isobutyl iodide using General Procedure8-G to afford1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

[2498] Step B: Following General Procedures 8-D and 8-F and using theproduct from Step A,3-amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one wasprepared.

[2499] Step C: The product from Step B and N-Boc-L-alanine (Sigma) werecoupled using General Procedure D, followed by removal of the Boc groupusing General Procedure 8-J, to afford3-(N′-L-alaninyl)amino-1,3-dihydro-1-isobutyl-5-phenyl-2H-1,4-benzodiazepin-2-one.By substituting isopropyl iodide, n-propyl iodide, cyclopropylmethyliodide and ethyl iodide for isobutyl iodide in Step A above, thefollowing additional intermediates were prepared:

[2500]3-(N′-L-alaninyl)amino-1,3-dihydro-1-isopropyl-5-phenyl-2H-1,4-benzodiazepin-2-one

[2501]3-(N′-L-alaninyl)amino-1,3-dihydro-1-propyl-5-phenyl-2H-1,4-benzodiazepin-2-one

[2502]3-(N′-L-alaninyl)amino-1,3-dihydro-1-cyclopropylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one

[2503]3-(N′-L-alaninyl)amino-1,3-dihydro-1-ethyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

Example 8-M Synthesis of3-(N′-L-Alaninyl)amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one

[2504] Step A: 1,3,4,5-Tetrahydro-5-phenyl-2H-1,5-benzodiazepin-2-one(CAS No. 32900-17-7) was methylated using General Procedure 8-I toafford 1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one.

[2505] Step B: Following General Procedures 8-E and 8-F and using theproduct from Step A,3-amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-onewas prepared.

[2506] Step C: The product from Step B and N-Boc-L-alanine (Sigma) werecoupled using General Procedure D, followed by removal of the Boc groupusing General Procedure 8-N, to afford3-(N′-L-alaninyl)amino-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one.

Example 8-N Synthesis of3-(N′-L-Alaninyl)amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2507]3-Amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(CAS No. 131604-75-6) was coupled with N-Boc-L-alanine (Sigma) usingGeneral Procedure D, followed by removal of the Boc group using GeneralProcedure 8-N, to afford the title compound.

Example 8-O Synthesis of3-((R)-Hydrazinopropionyl)amino-2,3-dihydro-1-methyl-5-phenyl)-1H-1,4-benzodiazepin-2-one

[2508] 3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-onewas coupled to (R)-N,N′-di-BOC-2-hydrazinopropionic acid (Example N)using General Procedure D. Removal of the Boc group using GeneralProcedure 5-B afforded the title compound.

Example 8-P Synthesis of3-Amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineStep A:—Synthesis of 2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2509] 2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No.49799-48-6) was prepared from 1,2-phenylenediamine (Aldrich) and malonicacid (Aldrich) using the procedure of Claremon, D. A.; et al, PCTApplication: WO 96-US8400 960603.

Step B:—Synthesis of2,4-Dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2510]2,4-Dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(CAS No. 113021-84-4) was prepared following General Procedure 8-M usingthe product from Step A and 2-iodopropane (Aldrich). Purification was byflash chromatography eluting with EtOAc/hexanes (3:7 gradient to 1:1),then recrystalization from EtOAc/hexanes.

Step C:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2511] Following General Procedure 8-K using the product from Step B,3-azido-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No.186490-50-6) was prepared as a white solid. The product was purified byflash chromatography eluting with hexanes/EtOAc (4:1) to provide aseparable 23:1 mixture of pseudo-axial/pseudo-equatorial azides. Thepure pseudo-axial azide was used in the next step.

Step D:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2512] Following General Procedure 8-L using the product from Step C,3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(CAS No. 186490-51-7) was prepared as a white solid. Purification was byflash chromatography eluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5).The isolated pseudo-axial amine atropisomer was completely converted tothe pseudo-equatorial amine atropisomer by heating in toluene to100-105° C. for 15 minutes, and the pseudo-equatorial amine atropisomerwas used in the next step. The isomers were distinguished by ¹H-NMR inCDCl₃. Selected ¹H-NMR (CDCl₃): Pseudo-axial amine 4.40 (s, 1H);Pseudo-equatorial amine 3.96 (s, 1H).

Example 8-Q Synthesis of3-(R-2-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride Step A:—Synthesis ofN-(t-Butoxycarbonyl)-R-2-thienylglycine

[2513] N-(t-Butoxycarbonyl)-R-2-thienylglycine (CAS No. 74462-03-1) wasprepared from L-α-(2-thienyl)glycine (Sigma) by the procedure describedin Bodansky, M. et al; The Practice of Peptide Synthesis; SpringerVerlag; 1994, p. 17.

Step B:—Synthesis of3-[N′-(t-Butoxycarbonyl)-R-2-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2514] Following General Procedure J above using the product fromExample 8-P and the product from Step A above,3-[N′-(t-butoxycarbonyl)-R-2-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (9:1 gradient to 5:1).

Step C:—Synthesis of3-(R-2-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

[2515] Following General Procedure 8-N above using the product from StepB, the title compound was prepared as a white solid.

Example 8-R Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride Step A:—Synthesis of2,4-Dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2516] 2,4-Dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(CAS No. 23954-54-3) was prepared following General Procedure 8-M usingthe product from Example 8-P, Step A and iodomethane (Aldrich). Thewhite solid product precipitated during partial concentration of thereaction after work-up, and was isolated by filtration.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2517] For this substrate, General Procedure 8-K was modified in thefollowing manner. Initially the product from Step A was suspended (not asolution) in THF at −78° C., and following addition of the KN(TMS)₂solution, this suspension was allowed to warm to −35° C. over a periodof 12 minutes, during which the suspension became a solution, and wasre-cooled to −78° C.; then treated as described in the GeneralProcedure.3-Azido-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas purified by flash chromatography eluting with CHCl₃/EtOAc (7:1),then trituration from hot CHCl₃ with hexanes and cooled to −23° C. Theproduct was isolated as a white solid.

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2518] Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. The crude product was used withoutfurther purification.

Step D:-13 Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2519] Following General Procedure I above using N-Boc-L-alanine(Novabiochem) and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (2:1 gradient to 1:1).

Step E:—Synthesis of3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

[2520] Following General Procedure 8-N above using the product from StepD, the title compound was prepared as an off-white amorphous solid.

Example 8-S Synthesis of3-(L-Alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride Step A:—Synthesis of2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2521]2,4-Dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared following General Procedure 8-M using the product fromExample 8-P, Step A and 1-iodo-2-methylpropane (Aldrich). Purificationwas by flash chromatography eluting with EtOAc/hexanes (3:7 gradient to1:1), then recrystalization from EtOAc/hexanes.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2522] Following General Procedure 8-K (a precipitate formed during theaddition of the KN(TMS)₂, but dissolved upon addition of the trisylazide) using the product from Step A,3-azido-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. The product was purified by flashchromatography eluting with hexanes/EtOAc (4:1) and a second flashchromatography eluting with CH₂Cl₂/hexanes/EtOAc (10:10:1 gradient to8:6:1).

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2523] Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. Purification was by flash chromatographyeluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5, with 5% NH₃ in theMeOH).

Step D:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2524] Following General Procedure I above using N-Boc-L-alanine(Novabiochem) and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (3:1 gradient to 3:2).

Step E:—Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

[2525] Following General Procedure 8-N above using the product from StepD, the title compound was prepared as an amorphous white solid.

Example 8-T Synthesis of3-(S-Phenylglycinyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride Step A:—Synthesis of3-[N′-(t-Butoxycarbonyl)-5-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2526] Following General Procedure J above using the product fromExample 8-S, Step C and the Boc-L-phenylglycine (Novabiochem, CAS No.2900-27-8),3-[N′-(t-butoxycarbonyl)-5-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (9:1 gradient to 5:1).

Step B:—Synthesis of3-(S-Phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

[2527] Following General Procedure 8-N above using the product from StepA,3-(S-phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride was prepared as an off-white solid.

Example 8-U Synthesis of3-(L-Alaninyl)amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride Step A:—Synthesis of2,4-Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2528]2,4-Dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared following General Procedure 8-M using the product fromExample 8-P, Step A, and (bromomethyl)cyclopropane (Lancaster).Purification was by flash chromatography eluting with EtOAc/hexanes (3:7gradient to straight EtOAc), then recrystalization from EtOAc/hexanes.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2529] For this substrate General Procedure 8-K was modified in thefollowing manner. Initially the product from Step A was suspended (not asolution) in THF at −78° C., and following addition of the KN(TMS)₂solution, this suspension was allowed to warm to −30° C., during whichthe suspension became a solution, and was re-cooled to −78° C. Uponre-cooling to −78° C. a precipitate began to form, therefore thereaction flask containing the mixture was partially raised above thecooling bath until the internal temperature rose to −50° C.; then thetrisyl azide solution was added. The cooling bath was removed and themixture allowed to warm to −20° C. whereupon the mixture had become anearly homogenous solution, and the AcOH was added. Then, treated asdescribed in the general procedure.3-Azido-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas purified by trituration with hot to room temperature EtOAc, followedby recrystalization from hot to −23° C. CHCl₃/EtOAc/EtOH (5:5:1) andisolated as a white solid.

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2530] Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. Purification was by flash chromatographyeluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5, with 5% NH₃ in theMeOH) followed by recrystalization from warm CH₂Cl₂/hexanes (1:1) to−23° C.

Step D:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2531] Following General Procedure I above using N-Boc-L-alanine(Novabiochem) and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (3:1 gradient to 2:1).

Step E:—Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

[2532] Following General Procedure 8-N above using the product from StepD, the title compound was prepared as an off-white solid.

Example 8-V Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride Step A:—Synthesis of2,4-Dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2533] To a stirred suspension of the product from Example 8-P, Step A(1.0 eq., 17.08 g) in DMSO (500 mL) at room temperature was addedneopentyl iodide (43.01 g, 2.24 eq., Aldrich) and Cs₂CO₃ (72.65 g, 2.3eq., Aldrich). The resulting mixture was heated to 75° C. for 30minutes, then additional Cs₂CO₃ (31.59 g, 1.0 eq.) was added and themixture rapidly stirred at 75° C. for 6 hours. The mixture was allowedto cool and H₂O (500 mL) and EtOAc (1000 mL) were added. The phases werepartitioned and the organic phase washed with H₂O (1×500 mL), 1 M aq.HCl (2×500 mL), and brine (1×500 mL). Then, the organic phase was driedover MgSO₄, filtered, concentrated, and purified by flash chromatographyeluting with hexanes/EtOAc (3:2 gradient to 2:3) to provide2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineas a white solid.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2534] Following General Procedure 8-K using the product from Step A,3-azido-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. The product was purified by flashchromatography eluting with hexanes/CH₂Cl₂/EtOAc (10:5:1 gradient to5:5:1) to provide a separable 13:1 mixture ofpseudo-axial/pseudo-equatorial azides. The pure pseudo-axial azide wasused in the next step. Selected ¹H-NMR (CDCl₃): Pseudo-axial azide 5.12(s, 1H); Pseudo-equatorial azide 4.03 (s, 1H).

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2535] Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. Purification was by flash chromatographyeluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5, with 5% NH₃ in theMeOH). The isolated white solid product was identified as a ˜4:1 mixtureof pseudo-axial and pseudo-equatorial amines atropisomers by ¹H-NMR. Themixture was heated in toluene to 100° C. for 20 minutes, thenre-concentrated to provide the pure pseudo-equatorial amine atropisomer,as a white solid, and this was for the next step. Selected ¹H-NMR(CDCl₃): Pseudo-axial amine 4.59 (s, 1H); Pseudo-equatorial amine 4.03(s, 1H).

Step D:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2536] Following General Procedure I above using N-Boc-L-alanine(Novabiochem) and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (4:1 gradient to 5:2).

Step E:—Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

[2537] Following General Procedure 8-N above using the product from StepD, the title compound was prepared as an off-white solid.

Example 8-W Synthesis of3-(L-Alaninyl)amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride Step A:—Synthesis of2,4-Dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2538] This procedure is a modification of the procedure described inChan, D. M. T. Tetrahedron Lett. 1996, 37, 9013-9016. A mixture of theproduct from Example 8-P, Step A (1.0 eq., 7.50 g), Ph₃Bi (2.2 eq.,41.26 g, Aldrich), Cu(OAc)₂ (2.0 eq., 15.48 g, Aldrich), Et₃N (2.0 eq.,8.62 g) in CH₂Cl₂ (100 mL) was stirred under N₂ at room temperature for6 days (monitoring by TLC). The solids were removed by filtrationthrough a plug of Celite rinsing with CH₂Cl₂/MeOH (3×75 mL). Thefiltrate was concentrated, dissolved in hot CH₂Cl₂/MeOH (9:1) andfiltered through a large plug of silica gel eluting with CH₂Cl₂/MeOH(9:1, 2L). The filtrate was concentrated and the residue purified byflash chromatography eluting with straight CH₂Cl₂ gradient toCH₂Cl₂/MeOH (9:1).2,4-Dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinecrystallized during concentration of the fractions containing theproduct, and was isolated by filtration as a white solid.

Step B:—Synthesis of3-Azido-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2539] For this substrate, General Procedure 8-K was modified in thefollowing manner. Initially the product from Step A was suspended (not asolution) in THF at −70° C., and following addition of the KN(TMS)₂solution, this suspension was allowed to warm to −20° C. over a periodof 10 minutes, during which the suspension became a solution, and wasre-cooled to −70° C.; then treated as described in the generalprocedure. The title compound was purified by trituration with hotCHCl₃/hexanes (1:1) to yield3-azido-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineas a white solid.

Step C:—Synthesis of3-Amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2540] Following General Procedure 8-L using the product from Step B,3-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white solid. Purification was by flash chromatographyeluting with CH₂Cl₂/MeOH (98:2 gradient to 95:5, with 5% NH₃ in theMeOH).

Step D:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2541] Following General Procedure I above using N-Boc-L-alanine(Novabiochem) and the product from Step C,3-[N′-(t-butoxycarbonyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared as a white foam. Purification was by flash chromatographyeluting with CH₂Cl₂/EtOAc (4:1 gradient to 3:1).

Step E:—Synthesis of3-(L-Alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineHydrochloride

[2542] Following General Procedure 8-N above using the product from StepD, the title compound was prepared as a white amorphous solid.

Example 8-X Synthesis of3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2543] Following the method of R. G. Sherrill et al., J. Org. Chem.,1995, 60, 730-734 and using glacial acetic acid and HBr gas, the titlecompound was prepared.

Example 8-Y Synthesis of3-(L-Valinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-oneStep A—Synthesis of3-[N′-(tert-Butylcarbamate)-L-valinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2544](S)-3-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate (Example8-B, Step A) was free based by partitioning between methylene chlorideand 1M potassium carbonate. The free amine was then coupled withN-Boc-valine following General Procedure D to give the title compound.

[2545] C₂₆H₃₂N₄O₄ (MW 464.62); mass spectroscopy 464.3.

[2546] Anal. Calcd for C₂₆H₃₂N₄O₄: C, 67.22; H, 6.94; N, 12.06. Found:C, 67.29; H, 6.79; N, 11.20.

Step B—Synthesis of3-(L-valinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2547] Following General Procedure 8-C and using3-[N′-(tert-butylcarbamate)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one,the title compound was prepared as a white foam.

[2548] C₂₁H₂₃N₄O₂ (MW 363.48); mass spectroscopy (M+H) 364.2.

Example 8-Z Synthesis of3-(L-tert-Leucinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-oneStep A—Synthesis of3-[N′-(tert-Butylcarbamate)-L-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2549](S)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-methanesulfonate (Example8-B, Step A) was free based by partitioning between methylene chlorideand 1M potassium carbonate. The free amine was then coupled withN-Boc-tert-leucine following General Procedure D to give the titlecompound.

[2550] C₂₇H₃₅N₄O₄ (MW 479.66); mass spectroscopy 479.

Step B—Synthesis of3-(L-tert-Leucinyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2551] Following General Procedure 8-C and using3-[N′-(tert-butylcarbamate)-L-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2-one,the title compound was prepared as a white foam.

[2552] Anal. Calcd for C₂₂H₂₅N₄O₂.0.5H₂O: C, 68.19; H, 7.02; N, 14.40.Found: C, 68.24; H, 7.00; N, 14.00.

Example 8-AA Synthesis of3-(L-Alaninyl)-amino-2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepine

[2553] 2,3-Dihydro-1,5-dimethyl-1H-1,4-benzodiazepine was preparedfollowing General Procedures 8-I (using methyl iodide), 8-D and 8-F.Coupling of this intermediate with Boc-L-alanine (Novo) using GeneralProcedure D, followed by deprotection using General Procedure 5-Bafforded the title compound which was used without further purification.

Example 8-AB Synthesis of3-(L-3-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepineStep A:—Synthesis of N-(t-Butoxycarbonyl)-L-3-thienylglycine

[2554] N-(t-Butoxycarbonyl)-L-3-thienylglycine was prepared fromL-α-(3-thienyl)glycine (Sigma) by the procedure described in Bodansky,M. et al; The Practice of Peptide Synthesis; Springer Verlag; 1994, p.17.

Step B:—Synthesis of3-[N′-(t-Butoxycarbonyl)-L-3-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2555] Following General Procedure D above using the product fromExample 8-V, Step C and the product from Step A above,3-[N′-(t-butoxycarbonyl)-L-3-thienylglycinyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinewas prepared.

Step C:—Synthesis of3-(L-3-Thienylglycinyl)amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2556] Following General Procedure 8-N above using the product from StepB, the title compound was prepared.

Example 8-1 Synthesis of3-(3,5-Difluorophenylacetyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2557] Following General Procedure A above using3,5-difluorophenylacetic acid (Oakwood) and3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-X), the title compound was prepared as a solid having amelting point of 236-239° C. The reaction was monitored by tlc on silicagel (Rf=0.7 in 10% methanol/dichloromethane) and purification was bysilica gel chromatography using 10% methanol/dichloromethane as theeluant.

[2558] NMR data was as follows:

[2559]¹H-nmr (CDCl₃): δ=7.4 (m, 9H), 6.90 (dd, J=6.0, 2.2, 2H), 6.73(dt, J=6.6, 2.2, 2.2, 6.6, 1H), 5.50 (d, J=7.7, 1H), 3.68 (s, 2H), 3.46(s, 3H).

[2560]¹³C-nmr (CDCl₃): δ=172.9, 165.2, 163.5, 138.3, 133.6, 127.7,126.4, 125.4, 124.6, 123.9, 120.3, 117.2, 108.2, 107.9; 98.4, 62.8,38.6, 30.9.

[2561] C₂₄H₁₉N₃O₂F (MW=419); mass spectroscopy (MH⁺) 420.

Example 8-2 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2562] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one(prepared as described in Example 8-X using ethyl iodide), the titlecompound was prepared as a solid having a melting point of 155-158° C.The reaction was monitored by tlc on silica gel (Rf=0.48 in 10%methanol/dichloromethane) and purification was by silica gelchromatography using 10% methanol/dichloromethane as the eluant,followed by recrystallization from diethyl ether.

[2563] NMR data was as follows:

[2564]¹H-nmr (CDCl₃): δ=7/73 (d, J=7.7, 1H), 7.4 (m, 9H), 6.86 (m, 2H),6.68 (m, 1H), 6.58 (d, J=7.2, 1H), 5.43 (dd, J=2.7, 4.9, 2.7, 1H), 4.67(m, 1H), 4.3 (m, 1H), 3.7 (m, 1H), 3,52 (s, 2H), 1.46 (dd, J=6.6, 6.6,3H), 1.10 (dt, J=7.1, 1.1, 6.0, 3H).

[2565]¹³C-nmr (CDCl₃): δ=167.8, 164.8, 163.4, 161.3, 136.7, 133.6,127.6, 126.4, 125.2, 124.0, 118.1, 107.8, 98.3, 95.5, 62.9, 44.7, 38.6,14.5, 8.7.

[2566] C₂₈H₂₆N₄O₃F₂ (MW=504); mass spectroscopy (MH⁺) 505.

Example 8-3 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-5-phenyl-1H-1,4benzodiazepin-2-one

[2567] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (CAS:10334347-1. Sherrill, R. G.; Sugg, E. E. J. Org. Chem. 1995, 60, 730.),the title compound was prepared as a white solid. Purification was bytrituration with 1: 1 ether/hexanes.

[2568] C₂₆H₂₁F₂N₄O₃ (MW=475.51); mass spectroscopy (MH⁺) 476.

[2569] Anal. Calcd for C₂₆H₂₁F₂N₄O₃: C, 65.54; H, 4.65; N, 11.76. Found:C, 65.37; H, 4.67; N, 11.63.

Example 8-4 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(1-piperidinyl)-1H-1,4-benzodiazepin-2-one

[2570] Following General Procedure D above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-1,3-dihydro-1-methyl-5-(1-piperidinyl)-2H-1,4-benzodiazepin-2-one(Example 8-A), the title compound was prepared as a white solid having amelting point of 154-160° C.

[2571] C₂₆H₂₉F₂N₅O₃ (MW=497.60); mass spectroscopy 497.

[2572] Anal. Calcd for C₂₆H₂₉F₂N₅O₃: C, 62.75; H, 5.89; N, 14.08. Found:C, 62.52; H, 5.81; N, 13.62.

Example 8-5 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2573] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-C), the title compound was prepared as a white solid having amelting point of 126.5-130° C.

[2574] C₂₇H₂₃ClF₂N₄O₃ (MW=524.1); mass spectroscopy 523.7.

[2575] Anal. calcd for C₂₇H₂₃ClF₂N₄O₃: C, 61.78; H, 4.42; N, 10.67.Found: C, 61.92; H, 4.52; N, 10.46.

Example 8-6 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2576] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one(Example 8-D), the title compound was prepared as a white solid.

[2577] C₂₇H₂₂BrF₃N₄O₃ (MW=587.43); mass spectroscopy 587.

[2578] Anal calcd for C₂₇H₂₂BrF₃N₄O₃: C, 55.21; H, 3.78; N, 9.54. Found:C, 55.25; H, 4.00; N, 9.72.

Example 8-7 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-N′-methyl-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2579] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(N′-methyl-L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-E), the title compound was prepared as a white solid.

[2580]¹H NMR (300 MHz, CDCl₃): δ=7.65 (1H, d, J=7.9 Hz), 7.59-7.34 (8H,m), 7.23 (1H, t, J=7.2 Hz), 6.84 (2H, d, J=6.0 Hz), 6.65 (1H, t, J=7.2Hz), 5.46 (1H, d, J=7.9 Hz), 5.42 (1H, d, J=7.2 Hz), 3.78 (2H, s), 3.47(3H, s), 3.02 (3H, s), 1.42 (3H, d, J=7.1 Hz).

[2581] C₂₈H₂₆F₂N₄O₃ (MW=505.2051); mass spectroscopy 505.2046.

Example 8-8 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one

[2582] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one(Example 8-F), the title compound was prepared as a white solid.

[2583] C₂₇H₂₂Cl₂F₂N₄O₃ (MW=559.43); mass spectroscopy 559.2.

[2584] Anal. calcd for C₂₇H₂₂Cl₂F₂N₄O₃: C, 57.97; H, 3.96; N, 10.02.Found: C, 57.99; H, 3.98; N, 9.92.

Example 8-9 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one

[2585] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-5-cylcohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one(Example 8-G), the title compound was prepared as a white solid.

[2586] C₂₇H₃₀F₂N₄O₃ (MW=497.2364); mass spectroscopy 497.2370.

Example 8-10 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one

[2587] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-H), the title compound was prepared as a yellow solid.

[2588]¹H NMR (300 MHz, CDCl₃): δ=8.44 (1H, dd, J=2.2, 9.0 Hz), 8.42 (1H,dd, J=2.3, 9.0 Hz), 8.23 (2H, d, J=2.6 Hz), 7.73 (2H, m), 7.56-7.40(12H, m), 6.83 (4H, m), 6.69 (2H, m), 6.37 (2H, apt, J=7.8 Hz), 5.45(1H, d, J=7.7 Hz), 5.44 (1H, d, J=7.7 Hz), 4.71 (2H, m), 3.56 (2H, s),3.55 (2H, s), 3.52 (3H, s), 3.51 (3H, s), 1.47 (3H, d, J=7.0 Hz), 1.46(3H, d, J=7.0 Hz).

[2589] C₂₇H₂₃F₂N₅O₅ (M+H=536.1747); mass spectroscopy found 536.1749.

Example 8-11 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2590] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one(Example 8-I), the title compound was prepared as a white solid having amelting point of 185-188° C.

[2591] C₂₇H₂₃F₃N₄O₃ (MW=508.54); mass spectroscopy found (M+H) 509.3.

[2592] Anal. calcd for C₂₇H₂₃F₃N₄O₃: C, 63.78; H, 4.53; N, 11.02. Found:C, 63.99; H, 4.49; N, 10.84.

Example 8-12 Synthesis of3-[N′-(3,5-Difluorophenyl-α-hydroxyacetyl)-L-valinyl]-amino2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2593] Following General Procedure D above usingS-(+)-3,5-difluoromandelic acid (Example L) and3-(L-valinyl)-amino-2,3-dihydro-1-methyl-5-1H-1,4-benzodiazepin-2-one(Example 8-Y), the title compound was prepared as a white solid.

[2594] C₂₉H₂₈F₂N₄O₄ (MW=534.61); mass spectroscopy found (M+H) 535.3.

[2595] Anal. calcd for C₂₉H₂₈F₂N₄O₄: C, 65.16; H, 5.28; N, 10.48. Found:C, 65.34; H, 5.43; N, 10.35.

Example 8-13 Synthesis of3-[N′-(3,5-Difluorophenyl-α-hydroxyacetyl)-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2596] Following General Procedure D above usingS-(+)-3,5-difluoromandelic acid (Example L) and3-(ten-leucinyl)-amino-2,3-dihydro-1-methyl-5-1H-1,4-benzodiazepin-2-one(Example 8-Z), the title compound was prepared as a white solid.

[2597] C₃₀H₃₀F₂N₄O₄ (MW=548.64); mass spectroscopy found (M+H) 549.3.

[2598] Anal. calcd for C₃₀H₃₀F₂N₄O₄: C, 65.68; H, 5.51; N, 10.21. Found:C, 65.38; H, 5.44; N, 10.14.

Example 8-14 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one

[2599] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one(Example 8-J), the title compound was prepared as an off white solid.

[2600] C₂₇H₂₃F₃N₄O₃ (MW=508.50); mass spectroscopy found (M+H) 509.3.

[2601]¹H NMR (300 MHz, CDCl₃): δ=7.65-7.53 (4H, m), 7.42-7.24 (12H, m),7.22-7.14 (2H, m), 6.87-6.81 (4H, m), 6.75-6.65 (2H, m), 6.29 (1H, d,J=6.6 Hz), 6.21 (1H, d, J=7.2 Hz), 5.45 (1H, d, J=7.8 Hz), 5.44 (1H, d,J=7.5 Hz), 4.67 (2H, m), 3.57 (2H, s), 3.55 (2H, s), 3.474 (3H, s),3.468 (3H, s), 1.48 (3H, d, J=7.2 Hz), 1.47 (3H, d, J=6.8 Hz).

Example 8-15 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4benzodiazepin-2-one

[2602] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one(Example 8-K), the title compound was prepared as an off-white solid.

[2603] C₂₇H₂₃F₃N₄O₃ (MW=508.50); mass spectroscopy found (M+H) 509.7.

[2604] Anal. calcd for C₂₇H₂₃F₃N₄O₃: C, 63.78; H, 4.56; N, 11.01. Found:C, 64.09; H, 4.81; N, 10.40.

Example 8-16 Synthesis of3-[N′-(Cyclopentyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4benzodiazepin-2-one

[2605] Following General Procedure D above using(±)-α-hydroxy-cyclopentylacetic acid (Example P) and3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-1H-1,4-benzodiazepin-2-one(Example 8-B), the title compound was prepared as a white solid.

[2606] Isomer 1:

[2607] C₂₆H₃₀N₄O₄ (MW=462.60); mass spectroscopy found (M+H) 463.6.

[2608] Anal. calcd for C₂₆H₃₀N₄O₄: C, 67.51; H, 6.54; N, 12.11. Found:C, 67.78; H, 6.65; N, 12.29.

[2609] Isomer 2:

[2610] C₂₆H₃₀N₄O₄ (MW=462.60); mass spectroscopy found (M+H) 463.4.

[2611] Anal. calcd for C₂₆H₃₀N₄O₄: C, 67.51; H, 6.54; N, 12.11. Found:C, 67.74; H, 6.56; N, 11.81.

Example 8-17 Synthesis of3-[N′-(Cyclopentyl-α-hydroxyacetyl)-L-valinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2612] Following General Procedure D above using(±)-α-hydroxy-cyclopentylacetic acid (Example P) and3-(L-valinyl)-amino-2,3-dihydro-1-methyl-5-1H-1,4-benzodiazepin-2-one(Example 8-B), the title compound was prepared as a white solid.

[2613] Isomer 1:

[2614] C₂₈H₃₄N₄O₄ (MW=490.66); mass spectroscopy found (M+H) 491.4.

[2615] Isomer 2:

[2616] C₂₈H₃₄N₄O₄ (MW=490.66); mass spectroscopy found (M+H) 491.4.

Example 8-18 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepin-2-one

[2617] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepin-2-one(Example 8-AA), the title compound was prepared as a solid (mp.=222-223°C.). The product was purified by slurrying in ether.

[2618] MW=429; mass spectroscopy found (M+H) 429.

[2619] Anal. calcd: C, 61.67; H, 5.18; N, 13.08. Found: C, 61.43; H,5.17; N, 12.79.

Example 8-19 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-isobutyl-5-phenyl)-1H-1,4-benzodiazepin-2-one

[2620] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)-amino-2,3-dihydro-1-isobutyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-L), the title compound was prepared as a solid (mp.=210-211°C.). The product was purified by tituration from ether/hexanes.

[2621] C₃₀H₃₀F₂N₄O₃ (MW=532.23); mass spectroscopy found (M+H) 532.

[2622] Anal. calcd: C, 67.66; H, 5.68; N, 10.52. Found: C, 67.67; H,5.55; N, 10.34.

[2623] Purification by C 2000 chromatography, eluting with hexanes/ethylacetate (20:80) afforded the following isomers:

[2624] Isomer 1:

[2625] Melting Point: 202-203° C.

[2626] C₃₀H₃₀F₂N₄O₃ (MW=532.23); mass spectroscopy found (M+H) 532.23.

[2627] Isomer 2:

[2628] Melting Point: 211-212° C.

[2629] C₃₀H₃₀F₂N₄O₃ (MW=532.23); mass spectroscopy found (M+H) 532.

Example 8-20 Synthesis of3-[N′-(3,5-Difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2630] Following General Procedure D above using 3,5-difluoromandelicacid (Fluorochem) and3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-B), the title compound was prepared as a solid. The productwas purified by LC 2000 chromatography, eluting with hexanes/ethylacetate (20:80).

[2631] Isomer 1:

[2632] Melting Point: 240-241° C.

[2633] C₂₇H₂₄F₂N₄O₄ (MW=506.51); mass spectroscopy found (M+H) 506.

[2634] Anal. calcd for C₂₇H₂₄F₃N₄O₄: C, 64.03; H, 4.78; N, 11.06. Found:C, 64.31; H, 4.86; N, 11.04.

[2635] Isomer 2:

[2636] Melting Point: 128° C.

[2637] C₂₇H₂₄F₂N₄O₄ (MW=506.51); mass spectroscopy found (M+H) 506.

[2638] Anal. calcd for C₂₇H₂₄F₃N₄O₄: C, 64.03; H, 4.78; N, 11.06. Found:C, 63.92; H, 5.00; N, 10.88.

Example 8-21 Synthesis of3-[N′-(3,5-Difluorophenyl-α-oxoacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2639] Following General Procedure D above using3,5-difluoro-α-oxoacetic acid (Example O) and3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-B), the title compound was prepared as a solid (mp.=128-129°C.). The product was purified by LC 2000 chromatography, eluting withhexanes/ethyl acetate (30:70).

[2640] C₂₇H₂₂F₂N₄O₄ (MW=504); mass spectroscopy found (M+H) 503.9.

[2641] Optical Rotation: [α]=−113.64 @589; −333.33 @365 (c 1, MeOH).

[2642] Anal. calcd for C₂₇H₂₂F₃N₄O₄: C, 64.28; H, 4.40; N, 11.11. Found:C, 64.51; H, 4.54; N, 11.04.

Example 8-22 Synthesis of3-[N′-(2-Methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2643] Following General Procedure D above using 2-methylthioacetic acid(Aldrich) and3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-B), the title compound was prepared as a solid (mp.=205-206°C.). The product was purified by slurrying in hexanes/ether (1:1).

[2644] C₂₂H₂₄N₄O₃S (MW=424); mass spectroscopy found (M+H) 424.

[2645] Anal. calcd for C₂₂H₂₄N₄O₃S: C, 62.25; H, 5.70; N, 13.20. Found:C, 62.11; H, 5.89; N, 13.02.

Example 8-23 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-valinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4benzodiazepin-2-one

[2646] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-valinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-Y), the title compound was prepared as a solid (mp.=228-229°C.). The product was purified by slurrying in ether/hexanes (80:20).

[2647] C₂₉H₂₈F₂N₄O₃ (MW=518); mass spectroscopy found (M+H) 518.

[2648] Optical Rotation: [α]=−117.96 @589; −341.55 @365 (c 1, MeOH).

[2649] Anal. calcd for C₂₉H₂₈F₂N₄O₃: C, 67.17; H, 5.44; N, 10.8. Found:C, 67.45; H, 5.49; N, 10.61.

Example 8-24 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-tert-leucinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2650] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-tert-leucinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-Z), the title compound was prepared as a solid (mp.=221-222°C.). The product was purified by slurrying in ether.

[2651] C₃₀H₃₀F₂N₄O₃ (MW=532); mass spectroscopy found (M+H) 532.

[2652] Anal. calcd for C₃₀H₃₀F₂N₄O₃: C, 67.66; H, 5.68; N, 10.52. Found:C, 67.93; H, 5.95; N, 10.25.

Example 8-25 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2653] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)amino-2,3-dihydro-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-L), the title compound was prepared as a solid (mp.=208-209°C.). The product was purified by slurrying in ether/hexanes (1:1).

[2654] MW=518; mass spectroscopy found (M+H) 518.

[2655] Anal. calcd: C, 67.17; H, 5.44; N, 10.80. Found: C, 67.39; H,5.62; N, 10.84.

Example 8-26 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-cyclopropylmethyl-5-phenyl-1H-1,4benzodiazepin-2-one

[2656] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)amino-2,3-dihydro-1-cyclopropylmethyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-L), the title compound was prepared as a solid (mp.=203-205°C.). The product was purified by slurrying in ether/hexanes.

[2657] C₃₀H₂₈F₂N₄O₃ (MW=530.58); mass spectroscopy found (M+H) 530.

[2658] Anal. calcd for C₃₀H₂₈F₂N₄O₃: C, 67.91; H, 5.32; N, 10.56. Found:C, 68.14; H, 5.54; N, 10.62.

Example 8-27 Synthesis of3-[N′-(3,5-Difluorophenyl-α-fluoroacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2659] Following General Procedure D above using3,5-difluorophenyl-α-fluoroacetic acid (Example S) and3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(Example 8-Y), the title compound was prepared as a solid. The productwas purified by LC 2000 chromatography, eluting with hexanes/ethylacetate (35:65).

[2660] Isomer 1:

[2661] Melting Point: 119-120° C.

[2662] C₂₇H₂₃F₃N₄O₃ (MW=508); mass spectroscopy found (M+H) 508.

[2663] Optical Rotation: [α]=−115.62 @589; −292.09 @365 (c 1, MeOH).

[2664] Anal. calcd for C₂₇H₂₃F₃N₄O₃: C, 62.66; H, 4.67; N, 10.82. Found:C, 62.55; H, 4.74; N, 10.51.

[2665] Isomer 2:

[2666] Melting Point: 198-199° C.

[2667] C₂₇H₂₃F₃N₄O₃ (MW=508); mass spectroscopy found (M+H) 508.

[2668] Optical Rotation: [α]=−99.65 @589; −279.72 @365 (c 1, MeOH).

[2669] Anal. calcd for C₂₇H₂₃F₃N₄O₃: C, 62.66; H, 4.67; N, 10.82. Found:C, 62.40; H, 4.62; N, 10.84.

Examples 8-28 to 8-139

[2670] By following the procedures set forth above, the followingadditional compounds were prepared: 8-283-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-n-propyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-293-[N′-(3-methylbutyryl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-30 3-[N′-(3,5-difluorophenylacetyl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-313-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-323-[N′-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-333-[N′-(2-phenylthioacetyl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-343-[N′-(3-(4-methoxyphenyl)propionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-353-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-363-[N′-(4-cyclohexylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-373-[N′-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-383-[N′-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-393-[N′-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-403-[N′-(3,3-dimethylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one 8-413-[N′-(thien-2-yl-acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-423-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-433-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-443-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-453-[N′-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-463-[N′-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-473-[N′-(3,5-di(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2- one 8-483-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-493-[N′-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-503-[N′-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-513-[N′-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-523-[N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-533-[N′-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-543-[N′-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-553-[N′-(4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-563-[N′-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-573-[N′-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-603-[N′-(2,6-difluorophenyl)-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-613-[N′-(4-fluorophenyl)-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2- one 8-623-[N′-(2,5-difluorophenyl)-α-hydroxyacetyl-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-633-[N′-(2,4,6-trifluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-643-[N′-(2-trifluoromethyl-4-fluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-653-[N′-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-663-[N′-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-673-[N′-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-683-[N′-(phenyl-α-hydroxyacetyl-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-693-[N′-(4-chlorophenyl-α-hydroxyacetyl-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2- one 8-703-[N′-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-713-[N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-723-[N′-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-733-[N′-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-743-[N′-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-753-[N′-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-76 3-[N′-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2- one 8-773-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-783-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-79 3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-80 3-[N′-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-81 3-[N′-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-82 3-[N′-(3,5-di-(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-833-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-84 3-[N′-(2-cyclomethylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-85 3-[N′-(2,3,4,5 ,6-pentafluorophenyloxyacetyl-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-863-[N′-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-87 3-[N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3- dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-88 3-[N′-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-89 3-[N′-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-903-[N′-(4-(2-thienyl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-91 3-[N′-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-95 3-[N′-(2,6-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-963-[N′-(4-fluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-973-[N′-(2,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-983-[N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl]amino-2,3- dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-99 3-[N′-(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1003-[N′-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-101 3-[N′-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-10(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1023-[N′-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1033-[N′-(phenyl-α-hydroxyacetyl-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1043-[N′-(4-chlorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-105 3-[N′-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl-1H-1,4-benzodiazepin-2- one 8-1063-[N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1073-[N′-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-108 3-[N′-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1093-[N′-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-110 3-[N′-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-1H 3-[N′-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one 8-1123-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1133-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-114 3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-117 3-[N′-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-118 3-[N′-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1193-[N′-(2-thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-120 3-[N′-(2-phenyl-2-oxoacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-123 3-[N′-((3,4-difluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1243-[N′-((4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-125 3-[N′-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one 8-1303-[N′-(4-fluorophenyl-α-hydroxyacetyl-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1313-[N′-(2,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1353-[N′-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4- benzodiazepin-2-one8-136 3-[N′-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1373-[N′-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1383-[N′-(phenyl-α-hydroxyacetyl-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one 8-1393-[N′-(4-chlorophenyl-α-hydroxyacetyl-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

Example 8-140 Synthesis of3-[N′-(3,5-Difluorophenyl-α-hydroxyacetyl)-L-3-thienylglycinyl]amino-2,4-dioxo-1,5-bis(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2671] Following General Procedure D above using 3,5-difluoromandelicacid (Fluorochem) and3-(L-3-thienylglycinyl]amino-2,4-dioxo-1,5-bis(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(Example 8-AB), the title compound was prepared as a solid. The productwas purified by LC 2000 chromatography, eluting with hexanes/ethylacetate (1:1).

[2672] Isomer 1:

[2673] Melting Point: 191-192° C.

[2674] Optical Rotation: [α]=+21.47 @589; +52.17 @365 (c 1, MeOH).

[2675] C₃₃H₃₈F₂N₄O₅S (MW=640); mass spectroscopy found (M+H) 639.1;640.1.

[2676] Anal. calcd for C₃₃H₃₈F₂N₄O₅S: C, 61.68; H, 5.89; N, 8.74. Found:C, 61.87; H, 6.08; N, 8.84.

[2677] Isomer 2:

[2678] Melting Point: 230-231° C.

[2679] Optical Rotation: [α]=+59.26 @589; +200.0 @365 (c 1, MeOH).

[2680] C₃₃H₃₈F₂N₄O₅S (MW=640); mass spectroscopy found (M+H) 639.4;640.4.

[2681] Anal. calcd for C₃₃H₃₈F₂N₄O₅S: C, 61.68; H, 5.89; N, 8.74. Found:C, 62.01; H, 6.07; N, 8.52.

Example 8-141 Synthesis of3-[N′-(3,5-Difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2682] Following General Procedure D above using 3,5-difluoromandelicacid (Fluorochem) and3-(L-alaninyl)amino-2,4-dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(Example 8-N), the title compound was prepared as a solid. The productwas purified by LC 2000 chromatography, eluting with hexanes/ethylacetate (30:70).

[2683] Isomer 1:

[2684] Melting Point: 212-213° C.

[2685] Optical Rotation: [α]=+101.34 @589; +491.4 @365 (c 1, MeOH).

[2686] C₂₇H₂₄F₂N₄O₅ (MW=522.17); mass spectroscopy found (M+H) 523.3;521.3.

[2687] Isomer 2:

[2688] Melting Point: 282-283° C.

[2689] C₂₇H₂₄F₂N₄O₅ (MW=522.1793); exact mass spectroscopy found (M+)523.1800.

[2690] Isomer 3:

[2691] Melting Point: 147-148° C.

[2692] C₂₇H₂₄F₂N₄O₅ (MW=522.1793); exact mass spectroscopy found (M+)523.1793.

[2693] Isomer 4:

[2694] Melting Point: 255-256° C.

[2695] C₂₇H₂₄F₂N₄O₅ (MW=522.17); mass spectroscopy found (M+) 523.2.

[2696] Anal. calcd for C₂₇H₂₄F₂N₄O₅: C, 62.07; H, 4.63; N, 10.72. Found:C, 62.18; H, 4.84; N, 10.74.

Example 8-142 Synthesis of3-[N′-(3,5-Difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2-oxo-1-methyl-5-phenyl-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2697] Following General Procedure D above using 3,5-difluoromandelicacid (Fluorochem) and3-(L-alaninyl)amino-2-oxo-1-methyl-5-phenyl-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine(Example 8-M), the title compound was prepared as a solid. The productwas purified by LC 2000 chromatography, eluting with hexanes/ethylacetate (40:60).

[2698] Isomer 1:

[2699] Melting Point: 258-259° C.

[2700] C₂₇H₂₆F₂N₄O₄ (MW=508); mass spectroscopy found (M+H) 507; 508.

[2701] Anal. calcd for C₂₇H₂₆F₂N₄O₄: C, 63.77; H, 5.16; N, 11.02. Found:C, 63.84; H, 5.34; N, 10.96.

[2702] Isomer 2:

[2703] C₂₇H₂₆F₂N₄O₄ (MW=508); mass spectroscopy found (M+H) 507; 508.

[2704] Anal. calcd for C₂₇H₂₆F₂N₄O₄: C, 63.77; H, 5.16; N, 11.02. Found:C, 63.74; H, 5.38; N, 10.76.

[2705] Isomer 3:

[2706] Melting Point: 121-123° C.

[2707] C₂₇H₂₆F₂N₄O₄ (MW=508); mass spectroscopy found (M+H) 507; 508.

[2708] Anal. calcd for C₂₇H₂₆F₂N₄O₄: C, 63.77; H, 5.16; N, 11.02. Found:C, 63.55; H, 5.30; N, 10.74.

[2709] Isomer 4:

[2710] Melting Point: 204-205° C.

[2711] C₂₇H₂₆F₂N₄O₄ (MW=508); mass spectroscopy found (M+H) 507; 508.

[2712] Anal. calcd for C₂₇H₂₆F₂N₄O₄: C, 63.77; H, 5.16; N, 11.02. Found:C, 63.23; H, 5.24; N, 10.74.

Example 8-143 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-L-1H-imidazole[1,2-a]-6-phenyl-1,4-benzodiazepine

[2713] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)amino-L-1H-imidiazole[1,2-a]-6-phenyl-1,4-benzodiazepine(prepared by the methods described in Bock et al., Bioorganic andMedicinal Chemistry, Vol. 2, 987-988 (1994); J. Med. Chem., 1988, 31,176-181; and J. Org. Chem., 1987, 52, 3232), the title compound wasprepared as a solid. The product was purified by LC 2000 chromatography,eluting with methanol/dichloromethane (5:95).

[2714] Isomer 1:

[2715] Melting Point: 205-206° C.

[2716] Optical Rotation: [α]=−12.86 @589; −135.05 @365 (c 1, MeOH).

[2717] C₂₈H₂₃F₂N₅O₂ (MW=499); mass spectroscopy found (M+H) 499.1.

[2718] Anal. calcd for C₂₈H₂₃F₂N₅O₂: C, 67.33; H, 4.64; N, 14.02. Found:C, 67.49; H, 4.61; N, 13.77.

[2719] Isomer 2:

[2720] Melting Point: 151-153° C.

[2721] Optical Rotation: [α]=−37.41 @589; −114.71 @365 (c 1, MeOH).

[2722] C₂₈H₂₃F₂N₅O₂ (MW=499.1894); exact mass spectroscopy found (M+H)499.1898.

[2723] Anal. calcd for C₂₈H₂₃F₂N₅O₂: C, 67.33; H, 4.64; N, 14.02. Found:C, 63.43; H, 4.36; N, 13.10.

Example 8-144 Synthesis of4-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-L-1H-imidazole[1,2-a]-2,4-dihydro-6-phenyl-1,4-benzodiazepine

[2724] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)amino-L-1H-imidazole[1,2-a]-2,4-dihydro-6-phenyl-1,4-benzodiazepine(prepared by the methods described in Bock et al., Bioorganic andMedicinal Chemistry, Vol. 2, 987-988 (1994); J. Med. Chem., 1988, 31,176-181; and J. Org. Chem., 1987, 52, 3232), the title compound wasprepared as a solid. The product was purified by LC 2000 chromatography,eluting with methanol/dichloromethane (5:95).

[2725] Isomer 1:

[2726] Melting Point: 135-136° C.

[2727] Optical Rotation: [α]=+15.63 @589; −162.5 @365 (c 1, MeOH).

[2728] C₂₈H₂₅F₂N₅O₂ (MW=501.2); mass spectroscopy found (M+H) 501.1.

[2729] Anal. calcd for C₂₈H₂₅F₂N₅O₂: C, 67.06; H, 5.02; N, 13.96. Found:C, 62.9; H, 4.93; N, 12.53.

[2730] Isomer 2:

[2731] Melting Point: 162-165° C.

[2732] Optical Rotation: [α]=−28.66 @589; −76.43 @365 (c 1, MeOH).

[2733] C₂₈H₂₅F₂N₅O₂ (MW=502.2050); exact mass spectroscopy found (M+H)502.2050.

[2734] Anal. calcd for C₂₈H₂₅F₂N₅O₂: C, 67.06; H, 5.02; N, 13.96. Found:C, 62.70; H, 4.78; N, 12.69.

Example 8-145 Synthesis of4-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-L4H[1,2,4]triazole[4,3-a]-6phenyl-1,4-benzodiazepine

[2735] Following General Procedure D above using3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and3-(L-alaninyl)amino-L-4H[1,2,4]triazole[4,3-a]-6-phenyl-1,4-benzodiazepine(prepared by the methods described in Bock et al., Bioorganic andMedicinal Chemistry, Vol. 2, 987-988 (1994); J. Med. Chem., 1988, 31,176-181; and J. Org. Chem., 1987, 52, 3232), the title compound wasprepared as a solid (m.p.=165-167° C.). The product was purified by LC2000 chromatography, eluting with methanol/dichloromethane (4:96).

[2736] Optical Rotation: [α]=−34.63 @589; −138.53 @365 (c 1, MeOH).

[2737] C₂₇H₂₂F₂N₆O₂ (MW=500); mass spectroscopy found (M+H) 500.1.

[2738] Anal. calcd for C₂₇H₂₂F₂N₆O₂: C, 64.79; H, 4.43; N, 16.79. Found:C, 63.01; H, 4.73; N, 15.32.

Example 8-146 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,4dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2739] Following General Procedure I above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(Example 8-P), the title compound was prepared as a white solid (meltingpoint=232-233° C.). Purification was by flash chromatography elutingwith EtOAc/hexanes (4:1 gradient to 6:1). R_(f)=0.31 (4:1EtOAc/hexanes).

[2740] C₂₆H₃₀F₂N₄O₄ (MW 500.55); mass spectroscopy (MH+) 500.2

[2741] Anal. Calcd. for C₂₆H₃₀F₂N₄O₄: C, 62.39; H, 6.04; N, 11.19.Found: C, 62.62; H, 6.00; N, 11.21.

Example 8-147 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-(R)-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2742] Following General Procedure I above using3,5-difluorophenylacetic acid (Lancaster) and3-(R-2-thienylglycinyl)-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-Q), the title compound was prepared as anamorphous white solid. Purification was by flash chromatography elutingwith CH₂Cl₂/EtOAc (5:1 gradient to 4:1). R_(f)=0.34 (4:1 CH₂Cl₂/EtOAc).

[2743] C₂₉H₃₀F₂N₄O₄S (MW 568.65); mass spectroscopy (MH+) 568.

[2744] Anal. Calcd. for C₂₉H₃₀F₂N₄O₄S: C, 61.25; H, 5.32; N, 9.85.Found: C, 61.00; H, 5.42; N, 9.68.

Example 8-148 Synthesis of3-[N′-(Cyclopropylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2745] Following General Procedure I above using cyclopropylacetic acid(Lancaster) and the product from Example 8-Q, the title compound wasprepared as an amorphous white solid. Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (4:1 gradient to 5:2).R_(f)=0.26 (4:1 CH₂Cl₂/EtOAc).

[2746] C₂₆H₃₂N₄O₄S (MW 496.63); mass spectroscopy (MH+) 496.5

[2747] Anal. Calcd. for C₂₆H₃₂N₄O₄S: C, 62.88; H, 6.49; N, 11.28. Found:C, 62.65; H, 6.57; N, 11.55.

Example 8-149 Synthesis of3-[N′-(Cyclopentylacetyl)-R-2-thienylglycinyl]amino-2,4dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2748] Following General Procedure I above using cyclopentylacetic acid(Aldrich) and the product from Example 8-Q, the title compound wasprepared as an amorphous white solid. Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (5:1 gradient to 4:1).R_(f)=0.26 (4:1 CH₂Cl₂/EtOAc).

[2749] C₂₈H₃₆N₄O₄S (MW 524.69); mass spectroscopy (MH+) 524.5

[2750] Anal. Calcd. for C₂₈H₃₆N₄O₄S: C, 64.10; H, 6.92; N, 10.68. Found:C, 64.07; H, 6.91; N, 10.67.

Example 8-150 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2751] Following General Procedure I above using3,5-difluorophenylacetic acid (Lancaster) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-R), the title compound was prepared as a whitesolid (melting point=206-207° C.). Purification was by flashchromatography eluting with straight EtOAc gradient to EtOAc/Acetone(95:5). R_(f)=0.32 (EtOAc).

[2752] C₂₂H₂₂F₂N₄O₄ (MW 444.42); mass spectroscopy (MH+) 444.

[2753] Anal. Calcd. for C₂₂H₂₂F₂N₄O₄: C, 59.46; H, 4.99; N, 12.61.Found: C, 59.54; H, 5.09; N, 12.56.

Example 8-151 Synthesis of3-[N′-(3,5-Difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2754] Following General Procedure I above using 3,5-difluoromandelicacid (Lancaster) and the product from Example 8-R, the title compoundwas prepared as an amorphous white solid. Purification was by L.C. 2000eluting with straight EtOAc then flash chromatography eluting withCH₂Cl₂/Acetone (4:1 gradient to 3:1). R_(f)=0.39 and 0.34 (EtOAc).

[2755] C₂₂H₂₂F₂N₄O₅ (MW 460.44); mass spectroscopy (MH+) 461.0.

[2756] Anal. Calcd. for C₂₂H₂₂F₂N₄O₅: C, 57.39; H, 4.82; N, 12.17.Found: C, 57.16; H, 4.88; N, 11.97.

Example 8-152 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2757] Following General Procedure I above using3,5-difluorophenylacetic acid (Lancaster) and3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-S), the title compound was prepared as a whitesolid (melting point=197-198° C.). Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (2:1 gradient to 3:4).R_(f)=0.23 (CH₂Cl₂/EtOAc, 1:1).

[2758] C₂₈H₃₄F₂N₄O₄ (MW 528.60); mass spectroscopy (MH+) 528.

[2759] Anal. Calcd. for C₂₈H₃₄F₂N₄O₄: C, 63.62; H, 6.48; N, 10.60.Found: C, 63.75; H, 6.63; N, 10.67.

Example 8-153 Synthesis of3-[N′-(Cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2760] Following General Procedure I above using cyclopentylacetic acid(Aldrich) and3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-S), the title compound was prepared as anamorphous white solid. Purification was by flash chromatography elutingwith CH₂Cl₂/EtOAc (1:1). R_(f)=0.31 (CH₂Cl₂/EtOAc, 1:1).

[2761] C₂₇H₄₀N₄O₄ (MW 484.64); mass spectroscopy (MH+) 484.

[2762] Anal. Calcd. for C₂₇H₄₀N₄O₄: C, 66.92; H, 8.32; N, 11.56. Found:C, 66.86; H, 8.64; N, 11.41.

Example 8-154 Synthesis of3-[N′-(Cyclopropylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2763] Following General Procedure I above using cyclopropylacetic acid(Lancaster) and3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-S), the title compound was prepared as a whitesolid (melting point=190-191° C.). Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (1:1 gradient to 3:4) and asecond flash chromatography eluting with EtOAc/Toluene (7:3). R_(f)=0.28(EtOAc/Toluene, 7:3).

[2764] C₂₅H₃₆N₄O₄ (MW 456.59); mass spectroscopy (MH+) 456.1.

[2765] Anal. Calcd. for C₂₅H₃₆N₄O₄: C, 65.77; H, 7.95; N, 12.27. Found:C, 66.01; H, 8.03; N, 12.35.

Example 8-155 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-5-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2766] Following General Procedure I above using3,5-difluorophenylacetic acid (Lancaster) and3-(S-phenylglycinyl)-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-T), the title compound was prepared as a whitesolid (melting point=186-187° C.). Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (7:1 gradient to 4:1).R_(f)=0.39 (CH₂Cl₂/EtOAc, 7:1).

[2767] C₃₃H₃₆F₂N₄O₄ (MW 590.68); mass spectroscopy (MH+) 590.0.

[2768] Anal. Calcd. for C₃₃H₃₆F₂N₄O₄: C, 67.10; H, 6.14; N, 9.49. Found:C, 67.36; H, 6.38; N, 9.56.

Example 8-156 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,4dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2769] Following General Procedure I above using3,5-difluorophenylacetic acid (Lancaster) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-U), the title compound was prepared as a whitesolid (melting point=211-212° C.). Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (1:1 gradient to 2:3).R_(f)=0.44 (CH₂Cl₂IEtOAc, 1:1).

[2770] C₂₈H₃₀F₂N₄O₄ (MW 524.57); mass spectroscopy (MH+) 524.1.

[2771] Anal. Calcd. for C₂₈H₃₀F₂N₄O₄: C, 64.11; H, 5.76; N, 10.68.Found: C, 64.07; H, 5.79; N, 10.49.

Example 8-157 Synthesis of3-[N′-(Cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2772] Following General Procedure I above using cyclopentylacetic acid(Aldrich) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-U), the title compound was prepared as a whitefoam. Purification was by flash chromatography eluting with CH₂Cl₂/EtOAc(1:1 gradient to 2:3). R_(f)=0.50 (CH₂Cl₂/EtOAc, 1:1).

[2773] C₂₇H₃₆N₄O₄ (MW 480.61); mass spectroscopy (MH+) 481.2 and (MH−)479.2.

[2774] Anal. Calcd. for C₂₇H₃₆N₄O₄: C, 67.48; H, 7.55; N, 11.66. Found:C, 67.33; H, 7.57; N, 11.37.

Example 8-158 Synthesis of3-[N′-(Cyclopentyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2775] Following General Procedure I above usingcyclopentyl-α-hydroxyacetic acid (Example P) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-U), the title compound was prepared as a whitefoam. Purification was by L.C. 2000 eluting with CH₂Cl₂/EtOAc (1:1gradient to 1:2) then flash chromatography eluting with 2:1EtOAc/CH₂Cl₂. R_(f)=0.47 and 0.37 (CH₂Cl₂/EtOAc, 1:2).

[2776] C₂₇H₃₆N₄O₅ (MW 496.61); mass spectroscopy (MH+) 497.2 and (MH−)495.2

[2777] Anal. Calcd. for C₂₇H₃₆N₄O₅: C, 65.30; H, 7.31; N, 11.28. Found:C, 65.01; H, 7.35; N, 11.28.

Example 8-159 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2778] Following General Procedure I above using3,5-difluorophenylacetic acid (Lancaster) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-V), the title compound was prepared as a whitesolid (melting point=194-195° C.). Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (2:1 gradient to 3:2).R_(f)=0.46 (CH₂Cl₂/EtOAc, 2: 1).

[2779] C₃₀H₃₈F₂N₄O₄ (MW 556.66); mass spectroscopy (MH+) 557.0 (MH−)555.4.

[2780] Anal. Calcd. for C₃₀H₃₈F₂N₄O₄: C, 64.73; H, 6.88; N, 10.06.Found: C, 64.45; H, 6.82; N, 10.08.

Example 8-160 Synthesis of3-[N′-(3,5-Difluorophenyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2781] Following General Procedure I above using 3,5-difluoromandelicacid (Lancaster) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-V), the title compound was prepared as a whitesolid (melting point=116-126° C.). Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (1:1 gradient to 2:3).R_(f)=0.54 and 0.40 (CH₂Cl₂/EtOAc, 1:1).

[2782] C₃₀H₃₈F₂N₄O₅ (MW 572.66); mass spectroscopy (MH+) 573.4 (MH−)571.6.

[2783] Anal. Calcd. for C₃₀H₃₈F₂N₄O₅: C, 62.92; H, 6.69; N, 9.78. Found:C, 62.86; H, 6.54; N, 9.65.

Example 8-161 Synthesis of3-[N′-(Cyclopentylacetyl)-L-alaninyl]amino2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2784] Following General Procedure I above using cyclopentylacetic acid(Aldrich) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-V), the title compound was prepared as a whiteamorphous solid. Purification was by flash chromatography eluting withCH₂Cl₂/EtOAc (2:1 gradient to 3:2). R_(f)=0.29 (CH₂Cl₂/EtOAc, 2:1).

[2785] C₂₉H₄₄N₄O₄ (MW 512.70); mass spectroscopy (MH+) 513.6 (MH−)511.6.

[2786] Anal. Calcd. for C₂₉H₄₄N₄O₄: C, 67.94; H, 8.65; N, 10.93. Found:C, 68.18; H, 8.60; N, 10.68.

Example 8-162 Synthesis of3-[N′-(Cyclopentyl-α-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2787] Following General Procedure I above usingcyclopentyl-α-hydroxyacetic acid (Example P) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-V), the title compound was prepared as a whitesolid (melting point=119-129° C.). Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (1:1 gradient to 2:3).R_(f)=0.42 and 0.28 (CH₂Cl₂/EtOAc, 1:1).

[2788] C₂₉H₄₄N₄O₅ (MW 528.70); mass spectroscopy (MH+) 529.2 (MH−)527.4.

[2789] Anal. Calcd. for C₂₉H₄₄N₄O₅: C, 65.88; H, 8.39; N, 10.60. Found:C, 65.56; H, 8.03; N, 10.35.

Example 8-163 Synthesis of3-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2790] Following General Procedure I above using3;5-difluorophenylacetic acid (Lancaster) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-W), the title compound was prepared as a whitesolid (melting point=139-141° C.). Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (1:1). R_(f)=0.46(CH₂Cl₂/EtOAc, 1:1).

[2791] C₃₂H₂₆F₂N₄O₄ (MW 568.59); mass spectroscopy (MH+) 569.2 (MH−)567.4.

[2792] Anal. Calcd. for C₃₂H₂₆F₂N₄O₄: C, 67.60; H, 4.61; N, 9.85. Found:C, 67.39; H, 4.66; N, 9.60.

Example 8-164 Synthesis of3-[N′-(Cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2793] Following General Procedure I above using cyclopentylacetic acid(Aldrich) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-W), the title compound was prepared as anamorphous white solid. Purification was by flash chromatography elutingwith CH₂Cl₂/EtOAc (1:1). R_(f)=0.44 (CH₂Cl₂/EtOAc, 1:1).

[2794] C₃₁H₃₂N₄O₄ (MW 524.63); mass spectroscopy (MH+) 525.2 (MH−)523.2.

[2795] Anal. Calcd. for C₃₁H₃₂N₄O₄: C, 70.97; H, 6.15; N, 10.68. Found:C, 70.67; H, 5.98; N, 10.43.

Example 8-165 Synthesis of3-[N′-(Cyclopentyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[2796] Following General Procedure I above usingcyclopentyl-α-hydroxyacetic acid (Example P) and3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride (Example 8-W), the title compound was prepared as a whitesolid (melting point=139-149° C.). Purification was by flashchromatography eluting with CH₂Cl₂/EtOAc (1:2). R_(f)=0.50 and 0.39(CH₂Cl₂/EtOAc, 1:2).

[2797] C₃₁H₃₂N₄O₅ (MW 540.63); mass spectroscopy (MH+) 541.2 (MH−)539.6.

[2798] Anal. Calcd. for C₃₁H₃₂N₄O₅: C, 68.87; H, 5.97; N, 10.36. Found:C, 68.87; H, 5.88; N, 10.15.

Example 8-166 Synthesis of3-(N′-(3,5-Difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5phenyl-1H-1,4-benzodiazepin-2-one

[2799] Following General Procedure A above usingN-(3,5-difluorophenylacetyl)-L-alanine (Example B) and3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(prepared as described in Bock M. G.; DiPardo, R. M.; Evans, B. E.;Rittle, K. E.; Veber, D. F.; Freidinger, R. M.; Hirshfield, J.;Springer, J. P. J. Org. Chem. 1987, 52, 3232), the title compound wasprepared as a solid having a melting point of 152-160° C. The reactionwas monitored by tlc on silica gel (Rf=0.15 in 50% ethylacetate/hexanes) and purification was by silica gel chromatography.

[2800] NMR data was as follows:

[2801]¹H-nmr (CDCl₃): δ=7.70 (t, J=7.2, 7.2, 1H); 7.4 (m, 9H); 6.83 (d,J=5.5, 2H); 6.7 (m, 1H); 6.50 (d, J=7.1, 1H); 5.44 (dd, 2.8, 4.9, 2.8,1H); 4.7 (m, 1H); 3.53 (s, 2H); 3.45 (s, 3H); 1.46 (dd, J=4.4, 2.2, 4.9,3H).

[2802]¹³C-nmr (CDCl₃): δ=172.9, 167.8, 138.3, 133.4, 127.7, 126.5,126.3, 125.4, 123.9, 120.3, 117.2, 108.1, 107.8, 98.4, 63.0, 44.7, 40.1,38.4, 30.9, 14.5, 14.1.

[2803] C₂₇H₂₄F₂N₄O₃ (MW=490); mass spectroscopy (MH⁺) 491.

[2804] The title compound was resolved using a Daicel chiral column(2×25 cm, ID×L) (normal phase polysaccharide type; 10 micro particlesize). Using a gradient of 40% isopropanol/hexanes (4 mL/min flow ratefor 35 minutes), followed by 20% isopropanol/hexanes (3 mL/min), isomer1 and isomer 2 had retention times of 27.5 and 36.4 minutes,respectively.

Example 8-167 Synthesis of3-(N′-(3,5-Difluorophenyl-α-hydroxyacetyl)-L-alaninyl)amino-5H-pyrrolo[1,2-a][1,5]benzodiazepin-6(7H)-one

[2805] 5H-Pyrrolo[1,2-a][1,5]benzodiazepin-6(7H)-one (CAS No.63743-03-3) was methylated using General Procedure 8-I, aminated byazide transfer using General Procedure 8-D and azide reduction usingGeneral Procedure 8-F, and coupled to L-Boc-alanine (Sigma) usingGeneral Procedure D. The Boc group was then removed using GeneralProcedure 8-N and the diastereomers were separated by LC chromatography.Each isomer was separately coupled with (S)-(+)-3,5-difluoromandelicacid (Example L) using General Procedure D to give the title compound.

[2806] Isomer 1:

[2807] Melting point=239-240° C.

[2808] MW=469.1687; exact mass spectroscopy (M+) 469.1693.

[2809] Optical rotation: [α]=−121.18° @589 and −540.33° @365 (c=1,MeOH).

[2810] Isomer 2:

[2811] Melting point=144-145° C.

[2812] MW=469.1687; exact mass spectroscopy (M⁺) 469.1687.

[2813] Optical rotation: [α]=+64.66° @589 and +255.03° @365 (c=1, MeOH).

[2814] Using the following combinatorial procedures, the followingadditional intermediates and examples were prepared.

General Procedure C-A

[2815] To a 4 mL vial containing 60-100 mg (0.06-0.1 mmol) of polymerbound 1-(1-pyrrolidinyl propyl)-3-ethyl carbodiimide was added 2 mL of a0.015 mM stock solution of starting material 1 in DMF/chloroform and 1mL of a 0.0148 mM stock solution of starting material 2 in chloroform.The resulting slurry were shaken for 48 h and filtered. The filteredresin was washed with chloroform and the filtrate was concentrated todryness under vacuum. All product structures and purities were confirmedby HPLC using UV detection and IEX MS. Samples were submitted fortesting with out any further purification.

General Procedure C-B

[2816] To a 4 mL vial was added 840 uL of 0.05 mM stock solution ofstarting material 1 in DMF/chloroform, 100 uL of a 0.21 mM stocksolution of starting material 2 in chloroform and 100 uL of a 0.63 mMstock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide inchloroform. After allowing to stand undisturbed for 48 h, the reactionmixture was concentrated and the residue redissolved in 2 mL of a 10%methanol/methylene chloride solution. This solution was then filteredthrough a pre-washed (methanol) 500 mg SCX column (Varian SamplePreparation; Harbor City Calif.) using an additional 8 mL of the samesolvent. The filtrate was concentrated under reduced pressure and theresidue was dissolved in 20% methanol/methylene chloride and passedthrough a plug of silica gel (100 mg, Varian Sample Preparation). Thecollected filtrate was concentrated under reduced pressure and the crudeproducts were submitted for testing without further purification.Product structure and purity were confirmed by HPLC and IEX MS.

General Procedure C-C

[2817] To a 4 mL vial was added 540 uL of 0.05 mM stock solution ofstarting material 1 in DMF/chloroform, 100 uL of a 0.44 mM stocksolution of starting material 2 in chloroform and 100 uL of a 0.38 mMstock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide inchloroform. After standing undisturbed for 48 h, the reaction mixturewas concentrated and the residue redissolved in 2 mL of a 10%methanol/methylene chloride solution. This solution was then filteredthrough a pre-washed (methanol) 500 mg SCX column using an additional 8mL of the same solvent. The filtrate was concentrated under reducedpressure and the residue was dissolved in 20% methanol/methylenechloride and passed through a plug of silica gel (100 mg, Varian SamplePreparation). The collected filtrate was concentrated under reducedpressure and the crude products were submitted for testing withoutfurther purification. Product structure and purity were confirmed byHPLC and IEX MS.

General Procedure C-D

[2818] To a 4 mL vial was added 540 uL of 0.05 mM stock solution ofstarting material 1 in DMF / chloroform, 100 uL of a 0.44 mM stocksolution of starting material 2 in chloroform, 100 uL of a 0.38 mM stocksolution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroformand 100 uL of a 0.38 mM stock solution of PP-HOBt in DMF. After standingundisturbed for 48 h, the reaction mixture was concentrated and theresidue redissolved in 2 mL of a 10% methanol/methylene chloridesolution. This solution was then filtered through a pre-washed(methanol) 500 mg SCX column using an additional 8 mL of the samesolvent. The filtrate was concentrated under reduced pressure and theresidue was dissolved in 20% methanol/methylene chloride and passedthrough a plug of silica gel (100 mg, Varian Sample Preparation). Thecollected filtrate was concentrated under reduced pressure and the crudeproducts were submitted for testing without further purification.Product structure and purity were confirmed by HPLC and IEX MS.

General Procedure C-E

[2819] To a 4 mL vial was added 870 uL of 0.05 mM stock solution ofstarting material 1 in DMF/chloroform, 1000 uL of a 0.05 mM stocksolution of starting material 2 in chloroform, 1000 uL of a 0.05 mMstock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide inchloroform and 100 uL of a 0.48 mM stock solution of HOBt in DMF. Afterstanding undisturbed for 48 h, the reaction mixture was concentrated andthe residue redissolved in 2 mL of a 10% methanol/methylene chloridesolution. This solution was then filtered through a pre-washed(methanol) 500 mg SCX column using an additional 8 mL of the samesolvent. The filtrate was concentrated under a stream of nitrogen toapproximately ⅓ its original volume and then passed over a plug (200 mg)of AG 1-8×anion exchange resin (BioRad; Hercules, Calif.; Columns werepre-washed with 1N NaOH, water and methanol) using an additional 6 mL of10% methanol/methylene chloride solution. The resulting filtrate wasconcentrated under vacuum and the crude products were submitted fortesting without further purification. Product structure and purity wereconfirmed by HPLC and IEX MS.

General Procedure C-F

[2820] Starting material 1 (9.1 uL, 0.109 mmol) was added neat to amixture of starting material 2 (22.5 mg, 0.054 mmol) andpiperidinylmethyl polystyrene (45 mg, 3.6 mmol/g (Fluka)) in 1 mL ofmethylene. The mixture was shaken for 80 h at ambient temperatures andthen treated with methylisocyanate polystyrene (100 mg, 1.0 mmol/g(Novabiochem)) for 24 h with shaking. The reaction mixture was filteredand the resin washed with methylene chloride. The crude product wasloaded onto a 500 mg SCX ion exchange column (Varian SamplePreparation), washed 3× with 3 mL of methanol and then eluted with 4 mLof 2 M ammonia methanol. Further purification of the final product wasachieved using semi-preparative HPLC (0-100% acetonitrile (0.08 %TFA)/water (0.1% TFA); 25 mL/min.; 20×50 ODS-A column) to give 17 mg ofthe final product as an off white foam.

[2821] NMR data was as follows:

[2822]¹H NMR (300 MHz, CDCl₃) δ1.45-1.65 (m, 3H), 1.70-2.00 (m, 4H),2.55-2.80 (m, 4H), 3.25 (s, 2H), 3.50 (s, 3H), 4.654.80 (m, 1H),5.45-5.55 (m, 1H), 7.20-7.80 (m, 11H).

General Procedure C-G

[2823] To a 4 mL vial containing 0.03 mmol of starting material 2 wasadded 100 uL of 0.25 mM stock solution of starting material 1 inchloroform, 100 uL of a 0.3 mM stock solution of1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100 uLof a 0.3 mM stock solution of HOBt in DMF. After standing undisturbedfor 48 h, the reaction mixture was concentrated and the residueredissolved in 2 mL of a 10% methanol/methylene chloride solution. Thissolution was then filtered through a pre-washed (methanol) 500 mg SCXcolumn using an additional 8 mL of the same solvent. The filtrate wasconcentrated under a stream of nitrogen to approximately ⅓ its originalvolume and then passed over a plug (200 mg) of AG 1-8×anion exchangeresin (BioRad; Hercules, Calif.; Columns were pre-washed with 1N NaOH,water and methanol) using an additional 6 mL of 10% methanol/methylenechloride solution. The resulting filtrate was concentrated under vacuumand the crude products were submitted for testing without furtherpurification. Product structure and purity were confirmed by HPLC andIEX MS.

General Procedure C-H

[2824] The intermediates shown in Table C-1 (i.e., Starting material 2)were synthesized in parallel in using the following procedure:

[2825] Step A: To a solution of3-(tert-butoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one(CA No. 125:33692: 100 mg, 0.28 mmol) in 1 mL of anhydrous DMF was added600 uL of a solution of 0.5 M potassium bis(trimethylsilyl)amide (0.30mmol) in toluene. Neat alkyl halide (0.56 mmol; as indicated in TableC-1) was added immediately in one portion and the reaction mixture wasleft undisturbed overnight. When an alkyl chloride was used, 1equivalent of sodium iodide was added to the reaction mixture. Afterconcentration under reduced pressure, the crude reaction residue waspartitioned between methylene chloride (2 mL) and aqueous saturatedbicarbonate (2 mL) and then passed through a 5 g Extralut QE cartridge(EM Science; Gibbstown, N.J.) using 10 mL of methylene chloride. Theresulting filtrate was concentrated under reduced pressure and the crudeproduct was further purified using automated semi-preparative HPLC (YMC20×50 mm Silica column; gradient elution; 0-5% (5.5 min.), 5-20% (3.5min.), 20-100% (2 min.), 100% (4 min.) ethyl acetate/methylene chloride,flow rate of 25 mL/min.). Product provided the expected M+1 peak by IEXMS and were carried on without further purification andcharacterization.

[2826] Step B: The product obtained from Step A was dissolved in 5 mL ofa 15% TFA/methylene chloride solution and allowed to stand undisturbedfor 16 h. After concentration under reduced pressure, the TFA salt wasdissolved in methanol and loaded directly onto a 1 g SCX column. Thecolumn was washed 3× with 2 mL portions of methanol and the product waseluted from the column using 6 mL of 2.0 M solution of ammonia/methanol.After concentration under reduced pressure, the product werecharacterized by IEX MS and carried on without further purification.

[2827] Step C: To the crude product obtained from Step B (1.05 equiv.)was added sequentially a 0.3 mM stock solution of HOBt.H₂O (1.05 equiv.)in DMF, a 0.3 mM stock solution of N-t-BOC-L-alanine (1.0 equiv.) in THFand 0.3 mM stock solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.05 equiv.) in THF. After standing undisturbed for 24 h,the reaction mixture was concentrated and the residue redissolved in 2mL of a 10% methanol/methylene chloride solution. This solution was thenfiltered through a pre-washed (methanol) 1 g SCX (Varian SamplePreparation) column using an additional 8 mL of the same solvent. ForExample C-V a 1 g Si column (Varian Sample Preparation) was used). Thefiltrate was concentrated under a stream of nitrogen to approximately ⅓its original volume and then passed over a plug (500 mg) of AG 1-8×anionexchange resin (BioRad; Hercules, Calif.; Columns were pre-washed with1N NaOH, water and methanol) using an additional 10 mL of methanol. Theresulting filtrate was concentrated under reduced pressure and the crudeproduct was carried on without further purification aftercharacterization by IEX MS.

[2828] Step D: The crude product obtained from Step C was dissolved in 5mL of a 15% TFA/methylene chloride solution and allowed to standundisturbed for 16 h. After concentration under reduced pressure, theTFA salt was dissolved in methanol and loaded directly onto a 1 g SCXcolumn. The column was washed 3× with 2 mL portions of methanol and theproduct were eluted from the column using 6 mL of 2.0 M solution ofammonia/methanol. After concentration under reduced pressure, theproduct were characterized by IEX MS and carried on without furtherpurification. The intermediates prepared by this method are shown inTable C-A. TABLE C-A Intermediates Ex. Alkyl Halide Intermediate MS C-A3-Fluorobenzyl 3-(L-alaninyl)amino-5-phenyl- 431.1 bromide (Aldrich)2,3-dihydro-1-(3-fluoro- benzyl)-1H-1,4-benzo- diazepin-2-one C-B Benzylbromide 3-(L-alaninyl)amino-5-phenyl- 513.2 (Aldrich)2,3-dihydro-1-(benzyl)-1H- 1,4-benzodiazepin-2-one C-C tert-Butylbenzylbromide 3-(L-alaninyl)amino-5-phenyl- 469.2 (Aldrich)2,3-dihydro-1-(4-tert- butylbenzyl)-1H-1,4- benzodiazepin-2-one C-D2-Bromoethylcyclo- 3-(L-alaninyl)amino-5-phenyl- 433.2 hexane(Fairfield) 2,3-dihydro-1-(2- cyclohexylethyl)-1H-1,4-benzodiazepin-2-one C-E 1-Bromo-3,3-dimethyl-3-(L-alaninyl)amino-5-phenyl- 407.2 butane (Wiley) 2,3-dihydro-1-(3,3-dimethylbutyl)-1H-1,4- benzodiazepin-2-one C-F Methyl alpha-butane3-(L-alaninyl)amino-5-phenyl- 471.2 bromophenylacetate 2,3-dihydro-1-(1-(Aldrich) methoxycarbonyl-1- phenylmethyl)-1H-1,4- benzodiazepin-2-oneC-G 1-bromo-2-ethylbutane 3-(L-alaninyl)amino-5-phenyl- 407.2 (Aldrich)2,3-dihydro-1-(2-ethylbutyl)- 1H-1,4-benzodiazepin-2-one C-HBromomethyl- 3-(L-alaninyl)amino-5-phenyl- 419.2 cyclohexane2,3-dihydro-1- (Aldrich) (cyclohexylmethyl)-1H-1,4- benzodiazepin-2-oneC-I 2-(Bromoethyl)benzene 3-(L-alaninyl)amino-5-phenyl- 427.2 (Aldrich)2,3-dihydro-1-(2-phenyl- ethyl)-1H-1,4-benzodiazepin- 2-one C-J3-(Bromopropyl)benzene 3-(L-alaninyl)amino-5-phenyl- 441.2 (K and KLaboratories) 2,3-dihydro-1-(3-phenyl- propyl)-1H-1,4-benzo-diazepin-2-one C-K N-(2- 3-(L-alaninyl)amino-5-phenyl- 496.2Bromoethyl)phthalimide 2,3-dihydro-1-(2-(N- (Aldrich)phthalimidyl)ethyl)-1H- 1,4-benzodiazepin-2-one C-L 2-Phenylbenzylbromide 3-(L-alaninyl)amino-5-phenyl- 489.2 (Aldrich) 2,3-dihydro-1-(2-biphenylmethyl)-1H-1,4- benzodiazepin-2-one C-M Tetrahydrofurfuryl3-(L-alaninyl)amino-5-phenyl- 407.2 bromide (Lancaster)2,3-dihydro-1-((2- tetrahydrofuranyl)methyl)-1H- 1,4-benzodiazepin-2-oneC-N 2-Bromomethyl-1,4- 3-(L-alaninyl)amino-5-phenyl- 471.2 benzodioxane2,3-dihydro-1-(2-(1,4- (Acros) benzodioxanyl)methyl)-1H-1,4-benzodiazepin-2-one C-O 3-Bromomethyl-5-3-(L-alaninyl)amino-5-phenyl- 503.1 chlorobenzo[b]thiophene2,3-dihydro-1-((3-(5-chloro- (Maybridge) benzo[b]thienyl))methyl)-1H-1,4-benzodiazepin-2-one C-P 1-Bromopinacolone3-(L-alaninyl)amino-5-phenyl- 421.1 (Lancaster)2,3-dihydro-1-(3,3-dimethyl- 2-oxo-propyl)-1H-1,4- benzodiazepin-2-oneC-Q 5-(Bromo- 3-(L-alaninyl)amino-5-phenyl- 455.2 methyl)benzofurazan2,3-dihydro-1-(5- (Maybridge) benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one C-R 3-Phenoxypropyl3-(L-alaninyl)amino-5-phenyl- 457.2 bromide (Aldrich)2,3-dihydro-1-(3-phenoxy- propyl)-1H-1,4-benzo- diazepin-2-one C-S6-(Bromomethyl)-2-(tri- 3-(L-alaninyl)amino-5-phenyl- 533.2fluoromethyl)quinoline 2,3-dihydro-1-(6-(2- (Maybridge) trifluoromethyl-quinolinyl)methyl)-1H-1,4- benzodiazepin-2-one C-T1-bromo-2-methylbutane 3-(L-alaninyl)amino-5-phenyl- 393.2 (Aldrich)2,3-dihydro-1-(2-methyl- butyl)-1H-1,4-benzodiazepin- 2-one C-U Ethylbromide 3-(L-alaninyl)amino-5-phenyl- 351.2 (Aldrich)2,3-dihydro-1-(ethyl)-1H-1,4- benzodiazepin-2-one C-V 3-Picolyl chloride3-(L-alaninyl)amino-5-phenyl- 414.1 hydrochloride2,3-dihydro-1-(3-pyridyl- (Aldrich) methyl)-1H-1,4-benzo- diazepin-2-oneC-W 1-(2-Chloro- 3-(L-alaninyl)amino-5-phenyl- 482.2 acetyl)indoline2,3-dihydro-1-(2-oxo-2-(N- (Maybridge) indolinyl)ethyl)-1H-1,4-benzodiazepin-2-one C-Y 4-(Chloromethyl)-3,5-3-(L-alaninyl)amino-5-phenyl- 432.2 dimethylisoxazole2,3-dihydro-1-((4-(3,5- (Aldrich) dimethyl)isoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one. C-Z 2-Bromoethyl methyl3-(L-alaninyl)amino-5-phenyl- 381.2 ether (Aldrich)2,3-dihydro-1-(2-methoxy- ethyl)-1H-1,4-benzodiazepin- 2-one

General Procedure C-I

[2829] To a 4 mL vial containing 0.03 mmol of starting material 2 (fromGeneral Procedure C-H) was added 100 uL of 0.25 mM stock solution ofstarting material 1 in chloroform, 100 uL of a 0.3 mM stock solution of1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in chloroform and 100 uLof a 0.3 mM stock solution of HOBt in DMF. After standing undisturbedfor 48 h, the reaction mixture was concentrated and the residueredissolved in 2 mL of a 10% methanol/methylene chloride solution. Thissolution was then filtered through a pre-washed (methanol) 500 mg Sicolumn using an additional 8 mL of the same solvent. The filtrate wasconcentrated under a stream of nitrogen to approximately ⅓ its originalvolume and then passed over a plug (200 mg) of AG 1-8×anion exchangeresin (Columns were pre-washed with 1N NaOH, water and methanol) usingan additional 6 mL of 10% methanol/methylene chloride solution. Theresulting filtrate was concentrated under vacuum and the crude productswere submitted for testing without further purification. Productstructure and purity were confirmed by HPLC and IEX MS.

Example C-AA Synthesis of(S)-3-(L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-oneStep A: Synthesis of(S)-3-(N′-(tert-Butoxycarbonyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2830] To a solution of triethyl amine (519 uL, 3.8 mmol) and(S)-3-amino-5-phenyl-2-oxo-1,4-benzodiazepine (1.0 g, 3.8 mmol)(prepared according to the procedure of M. G. Bock et al., J. Org. Chem.1987, 52, 3232-3239) in 100 mL of anhydrous methylene chloride at −20°C. was added N-Boc-L-phenylglycine fluoride (Carpino et al, J. Org.Chem. 1991, 56, 2611-2614) in one portion. The reaction mixture wasstirred for 15 min. and quenched with saturated aqueous bicarbonate (10mL). The layers were separated, the organic layer washed sequentiallywith saturated aqueous bicarbonate, water and brine and then dried oversodium sulfate. Purification of the crude product using silica gelchromatography (10-50% ethyl acetate/hexane) gave 1.3 g (69%) of ahydroscopic white foam.

[2831] NMR data was as follows:

[2832]¹H NMR (300 MHz, CDCl₃): δ=1.35 (br s, 9H), 3.41 (s, 3H),5.30-5.45 (m, 2H), 5.75-5.95 (m, 1H), 7.15-7.75 (m, 15H).

[2833] IR (CDCl₃): 1709.7, 1676.6, 1489, 1166.3 cm⁻¹.

[2834] IEX MS (M+1): 498.0.

Step B: Synthesis of(S)-3-(L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2835](S)-3-(N′-(tert-Butoxycarbonyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(1.27 g, 2.55 mmol) was added to 50 mL of a stirring solution of 15% TFAin methylene chloride in one portion. After stirring 1 h, the reactionmixture was concentrated under reduced pressure and the residuedissolved in 100 mL of methylene chloride. This solution was washedtwice with saturated sodium bicarbonate, once with brine and then driedover sodium sulfate. Purification of the crude product using silica gelcolumn chromatography (5-10% methanol/methylene chloride) gave 743 mg(73%) of a very light green foam.

[2836] NMR data was as follows:

[2837]¹H NMR (CDCl₃): δ=2.05 (br s, 1H), 3.45 (s, 3H), 5.51 (d, J=8.39Hz, 1H), 7.15-7.70 (m, 14H), 8.60 (d, J=830 Hz, 1H).

[2838] IR (CDCl₃): 1673.3, 1601.1, 1506.1 cm⁻¹.

[2839] IEX MS (M+1): 399.2.

Example C-AB Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-oneStep A: Synthesis of3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

[2840] To a solution of3-(Benzoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one(Bock, M. G. et al, Tetrahedron Lett. 1987, 28, 939; 4.0 g, 10.4 mmol)in 40 mL of anhydrous DMF at 0° C. was added potassium tert-butoxide(1.51 g, 13.5 mmol) in one portion. The reaction mixture was stirred 20min. and α-bromoacetophenone (Lancaster; Windham, N.H.; 2.9 g, 14.6mmol) was added. The reaction mixture was warmed to room temperatureover 30 min. and then diluted with 100 mL of water and 200 mL ofmethylene chloride. The layers were separated. The organic layer wasextracted with water and dried over sodium sulfate. Purification of thecrude product by silica gel column chromatography (0-5% ethylacetate/methylene chloride) gave 4.2 g (81%) of an off white foam.

[2841] NMR data was as follows:

[2842]¹H NMR (300 MHz, CDCl₃): δ=5.16 (s, 2H), 5.34 (s, 2H), 5.50 (d,J=8.33 Hz, 1H), 6.70 (d, J=8.28 Hz, 1H), 7.20-7.70 (m, 12H), 7.91 (d,J=7.54 Hz, 2H).

[2843] IR (CHCl₃): 1706.04, 1685.3, 1505.9, 1489.1, 1450.3, 1244.7 cm⁻¹.

[2844] IEX MS (M+1): 504.3.

Step B: Synthesis of3-Amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

[2845] A solution of3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(3.7 g, 7.36 mmol) in 100 mL of anhydrous methylene chloride was cooledto 0° C. under nitrogen. A stream of anhydrous HBr gas was then bubbledthrough this solution for 1 h. The bubbler was removed and the reactionwas warmed to room temperature under nitrogen. After stirring 1 h thereaction was concentrated under vacuum and the residue was redissolvedin 20 mL of methylene chloride. The crude HBr salt of the product wasprecipitated from solution using 300 mL of anhydrous ether and collectedby filtration as a light yellow solid. After washing with ether , thesolid was dissolved in methylene chloride and saturated sodiumbicarbonate. The layers were separated and the organic layer wasextracted with saturated sodium bicarbonate. The combined aqueous layerswere then back extracted twice with methylene chloride. The combinedorganic layers were extracted once with water and dried over sodiumsulfate. After concentration under vacuum, 2.27 g of the product wasobtained as an orange foam which was carried on without furtherpurification.

[2846] NMR data was as follows:

[2847]¹H NMR (300 MHz, CDCl₃): δ=2.60 (br s, 2H), 4.72 (s, 1H), 5.34 (s,2H), 7.10-7.70 (m, 12H), 7.91 (d, J=7.60 Hz, 2H).

[2848] IEX MS (M+1): 370.2

Step C: Synthesis of3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

[2849] To a solution of HOBt-H₂O (697 mg, 5.16 mmol),N,N-diisopropylethylamine (900 uL, 5.16 mmol) and N-t-BOC-L-alanine (975mg, 5.16 mmol) in 20 mL of anhydrous THF at 0° C. was added1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCl; 986mg, 5.16 mmol) in one portion. After stirring 5 min., a solution of3-amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(2.0 g, 5.43 mmol) in 20 mL of anhydrous THF was added via syringe andthe reaction mixture was warmed to room temperature and stirredovernight. The reaction mixture was diluted with 200 mL methylenechloride, extracted sequentially with 10% citric acid, saturated sodiumbicarbonate, water and brine and then dried over sodium sulfate.Purification of the crude product using silica gel chromatography(10%-30% ethyl acetate/methylene chloride) gave 2.59 g (93%) of a whitefoam.

[2850] NMR data was as follows:

[2851]¹H NMR (300 MHz, CDCl₃): δ=1.30-1.60 (m, 12H), 4.35 (br s,1H),5.00-5.50 (m, 3H), 5.65-5.70 (m, 1H), 7.15-7.65 (m, 12H), 7.70-7.80 (m,1H), 7.85-7.95 (m, 1H).

[2852] IR (CHCl₃): 1705.8, 1678.8, 1488.7, 1450.2, 1230.4, 1164.4 cm⁻¹.

[2853] IEX MS (M+1): 541.2.

Step D: Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

[2854]3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(2.5 g, 4.63 mmol) was added to 100 mL of a stirring solution of 15%TFA/methylene chloride in one portion. After stirring 2 h, the reactionmixture was concentrated under reduced pressure and the residue wasdissolved in 150 mL of methylene chloride. This solution was washedtwice with saturated sodium bicarbonate, once with brine and then driedover sodium sulfate. Purification of the crude product using silica gelcolumn chromatography (1-10% methanol/methylene chloride) gave 1.91 g(94%) of the title compound as a white foam.

[2855] NMR data was as follows:

[2856]¹H NMR (300 MHz, CDCl₃): δ=1.30-1.50 (m, 3H), 1.80-2.20 (br s, 2H), 3.55-3.75 (m, 1H), 5.20-5.45 (m, 2H), 5.67 (t, J=7.48 Hz, 1H),7.20-7.65 (m, 12H), 7.90 (d, J=7.7 Hz, 2H), 8.80 (dd, J₁=25.09 Hz,J₂=8.33 Hz, 1H).

[2857] EX MS (M+1): 441.2.

Example C-AC Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-(4,4,4trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-oneStep A: Synthesis of3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

[2858] To a solution of3-(benzoxycarbonyl)amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one(3.7 g, 9.61 mmol) in 40 mL of anhydrous DMF at 0° C. was addedpotassium tert-butoxide (1.6 g, 14.4 mmol) in one portion. The reactionmixture was stirred 20 min. and 4,4,4-trifluoro-1-bromobutane(Lancaster; Windham, N.H.; 2.6 g, 13.4 mmol) was added. The reactionmixture was warmed to room temperature over 30 min. and then dilutedwith 100 mL of water and 200 mL of methylene chloride. The layers wereseparated. The organic layer was extracted with water and dried oversodium sulfate. Purification of the crude product by silica gel columnchromatography (0-3% ethyl acetate/methylene chloride) gave 1.52 g (32%)of an off white foam.

[2859] NMR data was as follows:

[2860]¹H NMR (300 MHz, CDCl₃): δ=1.50-2.10 (m, 4H), 3.70-3.90 (m, 1 H),4.354.55 (m, 1H), 5.15 (s, 2H), 5.33 (d, J=8.47 Hz, 1H), 6.67 (d, J=8.40Hz, 1H), 7.2-7.70 (m, 14H).

[2861] IR (CHCl₃): 1720.4, 1683.0, 1604.8, 1505.5, 1451.1, 1323.9,1254.5, 1148.4 cm⁻¹.

[2862] IEX MS (M+1): 496.3.

Step B: Synthesis of3-Amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4benzodiazepin-2-one

[2863] A solution of3-(benzoxycarbonyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(1.42 g, 2.87 mmol) in 50 mL of anhydrous methylene chloride was cooledto 0° C. under nitrogen. A stream of anhydrous HBr gas was slowlybubbled through the solution for 1 h. The bubbler was removed and thereaction was warmed to room temperature under nitrogen. After stirringfor 1 h, the reaction was concentrated under vacuum and the residue wasredissolved in 10 mL of methylene chloride. The crude HBr salt of theproduct was precipitated from solution using 90 mL of anhydrous etherand collected by filtration. After washing with ether, the HBr salt wasdissolved in methylene chloride and saturated sodium bicarbonate. Thelayers were separated and the organic layer was extracted with saturatedsodium bicarbonate. The combined aqueous layers were then back extractedtwice with methylene chloride. The combined organic layers wereextracted once with water and dried over sodium sulfate. Afterconcentration under vacuum, 1.06 g (100%) of the product was obtained asa white foam which was carried on without further purification.

[2864] NMR data was as follows:

[2865]¹H NMR (300 MHz, CDCl₃): δ=1.60-2.10 (m, 4H), 2.76 (br s, 2H),3.75-3.85 (m, 1H), 4.40-4.60 (m, 2H), 7.20-7.70 (m, 9H).

[2866] IEX MS (M+1): 362.1.

Step C: Synthesis of3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

[2867] To a solution of HOBt-H₂O (373 mg, 2.76 mmol),N,N-diisopropylethylamine (481 uL, 2.76 mmol) and N-t-BOC-L-alanine (522mg, 2.76 mmol) in 10 mL of anhydrous THF at 0° C. was added1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCl; 527mg, 2.76 mmol) in one portion. After stirring 5 min., a solution of3-amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(1.05 g, 2.91 mmol) in 10 mL of anhydrous THF was added via syringe andthe reaction mixture was warmed to room temperature and stirredovernight. The reaction mixture was diluted with 100 mL methylenechloride, extracted sequentially with 10% citric acid, saturated sodiumbicarbonate, water and brine and then dried over sodium sulfate.Purification of the crude product using silica gel chromatography(10%-30% ethyl acetate/methylene chloride) gave 1.28 g (83%) of a whitefoam.

[2868] NMR data was as follows:

[2869]¹H NMR (300 MHz, CDCl₃): δ=1.40-2.10 (m, 16H), 3.70-3.85 (m, 1 H),4.304.55 (m, 2H), 5.10 (br s, 1H), 5.45-5.55 (m, 1H), 7.25-7.80 (m,10H).

[2870] IR (CDCl₃): 1676.6, 1605.2, 1488.6, 1450.9, 1393.2, 1338.7,1324.9, 1253.8, 1150.4 cm⁻¹.

[2871] IEX MS (M+1): 533.1.

Step D: Synthesis of3-(L-Alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one

[2872]3-(N′-(tert-Butoxycarbonyl)-L-alaninyl)amino-2,3-dihydro-1-(4,4,4-trifluorobutyl)-5-phenyl-1H-1,4-benzodiazepin-2-one(1.21 g, 2.27 mmol) was added to 50 mL of a stirring solution of 15%TFA/methylene chloride in one portion. After stirring 2 h, the reactionmixture was concentrated under reduced pressure and the residue wasdissolved in 100 mL of methylene chloride. This solution was washedtwice with saturated sodium bicarbonate, once with brine and then driedover sodium sulfate. Purification of the crude product using silica gelcolumn chromatography (1-5% methanol/methylene chloride) gave 670 mg(68%) of a light pink foam.

[2873] NMR data was as follows:

[2874]¹H NMR (300 MHz, CDCl₃): δ=1.43 (t, J=7.0 Hz, 3H), 1.60-2.20 (m,7H), 3.60-3.85 (m, 2H), 4.35-4.55 (m, 1H), 5.51 (dd, J₁=8.36 Hz, J₂=2.48Hz, 1H), 7.20-7.70 (m, 9H), 8.80 (dd, J₁=27.73 Hz, J₂=8.34 Hz, 1H).

[2875] IEX MS (M+1): 433.2.

Example C-AD Synthesis of3-(N′-(Chloroacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one

[2876] A solution of3-(L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(20.0 mg, 0.0595 mmol), α-chloroacetyl chloride (5.9 uL, 0.0744 mmol)and piperidinylmethyl polystyrene (59.5 mg, 3.6 mmol/g (Fluka)) in 1 mLof methylene chloride were shaken for 20 min. Aminomethyl polystyrene(58 mg, 3.0 mmol/g (Advanced Chemtech)) was then added and the reactionmixture was shaken for an additional 15 min. and filtered. Removal ofthe solvent under reduced pressure provided 23.9 mg (98%) of the crudeproduct which was used without further purification.

[2877] NMR data was as follows:

[2878]¹H NMR (300 MHz, CDCl₃): δ=1.40-1.60 (m, 3H), 3.40-3.6 (m, 3H),4.1 (s, 2H), 4.60-4.80 (m, 1H), 5.45-5.50 (m, 1H), 7.20-7.90 (m, 11H).Using the procedures indicated, the compounds shown in Table C-1 wereprepared. TABLE C-1 Example General No. Compound Starting Material 1Starting Material 2 Procedure MS 8C-1 3-(N′-(3,4- 3,4-3-(L-alaninyl)amino-2,3- C-A 498.8 Methylenedioxyphenylacetyl-L-Methylenedioxyphenylacetic dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- acid 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B) benzodiazepin-2-one 8C-23-(N′-(2-Methoxyphenoxyacetyl)- 2-Methoxyphenoxyacetic3-(L-alaninyl)amino-2,3- C-A 500.8 L-alaninyl)amino-2,3-dihydro-1- aciddihydro-1-methyl-5-phenyl-1H methyl-5-phenyl-1H-1,4- (Lancaster)1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-3 3-(N′-(4-4-Isopropylphenoxyacetic 3-(L-alaninyl)amino-2,3- C-A 513.0Isopropylphenoxyacetyl-L- acid dihydro-1-methyl-5-phenyl-1Halaninyl)amino-2,3-dihydro-1- (Lancaster) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-43-(N′-(Ethoxyacetyl-L- Ethoxyacetic acid 3-(L-alaninyl)amino-2,3- C-A422.6 alaninyl)amino-2,3-dihydro-1- (Aldrich)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-53-(N′-(4-Phenoxyphenylacetyl)- 4-Phenoxyphenylacetic acid3-(L-alaninyl)amino-2,3- C-A 547.0 L-alaninyl)amino-2,3-dihydro-1-(Trans World) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-63-(N′-(4-Ethoxyphenylacetyl)-L- 4-Ethoxyphenylacetic acid3-(L-alaninyl)amino-2,3- C-A 501.1 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-73-(N′-(2,5- 2,5-Dimethoxyphenylacetic 3-(L-alaninyl)amino-2,3- C-A 514.8Dimethoxyphenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-83-(N′-(3,5-Difluorobenzoyl)-L- 3,5-Difluorobenzoic acid3-(L-alaninyl)amino-2,3- C-A 476.8 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-93-(N′-(o-Tolylacetyl)-L- o-Tolylacetic acid 3-(L-alaninyl)amino-2,3- C-A470.0 alaninyl)amino-2,3-dihydro-1- (Aldrich)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-103-(N′-(3,3-Diphenylpropionyl)- 3,3-Diphenylpropionic acid3-(L-alaninyl)amino-2,3- C-A 545.0 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-113-(N′-(3-Phenoxypropionyl)-L- 3-Phenoxypropionic acid3-(L-alaninyl)amino-2,3- C-A 485.0 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-123-(N′-(Indole-3-acetyl)-L- Indole-3-acetic acid 3-(L-alaninyl)amino-2,3-C-A 494.0 alaninyl)amino-2,3-dihydro-1- (Aldrich)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-133-(N′-(4- 4- 3-(L-alaninyl)amino-2,3- C-A 523.0(Trifluoromethyl)phenylacetyl)- (Trifluoromethyl)phenyl-dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1- aceticacid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Maybridge)(Example 8-B) benzodiazepin-2-one 8C-14 3-(N′-((4-Methylphenoxy)acetyl)-(4-Methylphenoxy)acetic 3-(L-alaninyl)amino-2,3- C-A 485.0L-alaninyl)amino-2,3-dihydro-1- acid dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- (Aldrich) 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example 8-B) 8C-16 3-(N′-(4- 4-3-(L-alaninyl)amino-2,3- C-A 500.8 (Hydroxymethyl)phenoxyacetyl)-(Hydroxymethyl)phenoxy- dihydro-1-methyl-5-phenyl-1H-L-alaninyl)amino-2,3-dihydro-1- acetic acid 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Sigma) (Example 8-B) benzodiazepin-2-one 8C-173-(N′-(2-Phenoxyphenylacetyl)- 2-Phenoxyphenylacetic acid3-(L-alaninyl)amino-2,3- C-A 546.8 L-alaninyl)amino-2,3-dihydro-1-(TransWorld) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-183-(N′-(3-Phenoxyphenylacetyl)- 3-Phenoxyphenylacetic acid3-(L-alaninyl)amino-2,3- C-A 547.0 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-193-(N′-(3,4- 3,4-dichlorophenoxyacetic 3-(L-alaninyl)amino-2,3- C-A 539.2dichlorophenoxyacetyl-L- acid dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-203-(N′-(4-Fluorophenoxyacetyl)- 4-Fluorophenoxyacetic acid3-(L-alaninyl)amino-2,3- C-A 489.0 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-213-(N′-(Methylthio)acetyl-L- (Methylthio)acetic acid3-(L-alaninyl)amino-2,3- C-A 424.8 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-S -phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-223-(N′-(Methoxyacetyl-L- Methoxyacetic acid 3-(L-alaninyl)amino-2,3- C-A409.0 alaninyl)amino-2,3-dihydro-1- (Aldrich)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-23(S)-3-(N′-(Phenoxyacetyl-L- Phenoxyacetic acid(S)-3-(L-alaninyl)amino-2,3 C-B 471.0 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-24(S)-3-(N′-(Phenylacetyl-L- Phenylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-B 455.0 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-25(S)-3-(N′-(2-Phenoxybutyryl)-1- 2-Phenoxybutyric acid(S)-3-(L-alaninyl)amino-2,3- C-B 498.8 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-26(S)-3-(N′-(3- 3-Methoxyphenoxyacetic (S)-3-(L-alaninyl)amino-2,3- C-B501.0 Methoxyphenoxyacetyl-L- acid dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-28(S)-3-(N′-(4- 4-Butoxyphenylacetic acid (S)-3-(L-alaninyl)amino-2,3 C-B526.8 Butoxyphenylacetyl-L- (Lancaster) dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-29(S)-3-(N′-(3-(2- 3-(2- (S)-3-(L-alaninyl)amino-2,3- C-B 498.8Methoxyphenyl)propionyl)-L- Methoxyphenyl)propionicdihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B)benzodiazepin-2-one 8C-30 (S)-3-(N′-(4-Fluorophenylacetyl)4-Fluorophenylacetic acid (S)-3-(L-alaninyl)amino-2,3 C-B 472.8L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-31 (S)-3-(N′-(Isopropoxylacetyl)-L- Isopropoxylaceticacid (S)-3-(L-alaninyl)amino-2,3- C-B 436.8alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-S -phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-32 (S)-3-(N′-(1-Phenyl-1H-tetrazole-1-Phenyl-1H-tetrazole-5- (S)-3-(L-alaninyl)amino-2,3- C-B 523.05-acetyl)-L-alaninyl)amino-2,3- acetic aciddihydro-1-methyl-5-phenyl-1H- dihydro-1-methyl-5-Phenyl-1H- (Raap, R.Can. J. Chem. 1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one 1968,46(13), 2255-61) (Example 8-B) 8C-33 (S)-3-(N′-(3-(3,4- 3-(3,4-(S)-3-(L-alaninyl)amino-2,3- C-B 513.2 methylenedioxyphenyl)propionyl)-methylenedioxyphenyl) dihydro-1-methyl-5-phenyl-1H-L-alaninyl)amino-2,3-dihydro- propionic acid 1,4-benzodiazepin-2-one1-methyl-5-phenyl-1H-1,4- (Apin) (Example 8-B) benzodiazepin-2-one 8C-34(S)-3-(N′-(3- 3-Cyclopentylpropionic acid (S)-3-(L-alaninyl)amino-2,3-C-B 461.0 Cyclopentylpropionyl)-L- (Aldrich)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-35 (S)-3-(N-(2-Cyclopentene-L-2-Cyclopentene-1-acetic (S)-3-(L-alaninyl)amino-2,3- C-B 445.0acetyl)-L-alaninyl)amino-2,3- acid dihydro-1-methyl-5-phenyl-1Hdihydro-1-methyl-5-phenyl-1H- (Aldrich) 1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example 8-B) 8C-36 (S)-3-(N′-(2-Chloro-6-2-Chloro-6- (S)-3-(L-alaninyl)amino-2,3- C-B 507.0fluororophenylacetyl)-L- fluorophenylacetic aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Aldrich)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-37 (S)-3-(N′-(Cyclohexylacetyl)-L-Cyclohexylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-B 461.0alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-38 (S)-3-(N′-(2,5- 2,5-Difluorophenylacetic(S)-3-(L-alaninyl)amino-2,3- C-B 491.2 Difluorophenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Aldrich)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-39 (S)-3-(N′- Pentafluorophenoxyacetic(S)-3-(L-alaninyl)amino-2,3- C-B 561.0 (Pentafluorophenoxyacetyl)-L-acid dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-(Aldrich) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-40 (S)-3-(N′-(3,5- 3,5-Dimethylphenoxyacetic(S)-3-(L-alaninyl)amino-2,3- C-B 498.8 Dimethylphenoxyacetyl-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-(Sigma-Aldrich Rare 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-Chemicals) (Example 8-B) benzodiazepin-2-one 8C-41(S)-3-(N′-(4-Chlorophenylacetyl)- 4-Chlorophenylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-B 489.2 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-42(S)-3-(N′-(3- 3-Chlorophenoxyacetic acid (S)-3-(L-alaninyl)amino-2,3-C-B 505.0 Chlorophenoxyacetyl-L- (Lancaster)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-43 (S)-3-(N′-(Benzo[b]thiophene-3-Benzo[b]thiophene-3- (S)-3-(L-alaninyl)amino-2,3 C-B 511.2acetyl)-L-alaninyl)amino-2,3- acetic acid dihydro-1-methyl-5-phenyl-1H-dihydro-1-methyl-5-phenyl-1H- (Lancaster) 1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example 8-B) 8C-44 (S)-3-(N′-(Benzoylformyl)-L-Benzoylformic acid (S)-3-(L-alaninyl)amino-2,3 C-B 468.8alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-45 (S)-3-(N′-(3,5- 3,5-Dimethoxyphenylacetic(S)-3-(L-alaninyl)amino-2,3- C-B 515.0 Dimethoxyphenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Aldrich)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-46 (S)-3-(N′-(2,5- 2,5-Dimethylphenylacetic(S)-3-(L-alaninyl)amino-2,3- C-B 483.2 Dimethylphenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Lancaster)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-47 (S)-3-(N′-(2,6- 2,6-Difluorophenylacetic(S)-3-(L-alaninyl)amino-2,3- C-B 491.2 Difluorophenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Aldrich)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-48 (S)-3-(N′-(2,4- 2,4-Difluorophenylacetic(S)-3-(L-alaninyl)amino-2,3- C-B 491.0 Difluorophenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Aldrich)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-49 (S)-3-(N′-(Mesitylacetyl)-L- Mesitylaceticacid (S)-3-(L-alaninyl)amino-2,3- C-B 497.0alaninyl)amino-2,3-dihydro-1- (Lancaster) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-50 (S)-3-(N-(4-Biphenylacetyl)-L- 4-Biphenylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-B 531.2 alaninyl)amino-2,3-dihydro-1-(Lancaster) dihydro-1-methyl-S -phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-51(S)-3-(N′-(3,4- 3,4-Difluorophenylacetic (S)-3-(L-alaninyl)amino-2,3-C-B 491.2 Difluorophenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-52(S)-3-(N′-(trans-Styrylacetyl)-L- trans-Styrylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-B 481.2 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-53(S)-3-(N′-(3-Benzoylpropionyl)- 3-Benzoylpropionic acid(S)-3-(L-alaninyl)amino-2,3- C-B 497.0 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-54(S)-3-(N′-(trans-3-Hexenoyl)-L- trans-3-Hexenoic acid(S)-3-(L-alaninyl)amino-2,3- C-B 433.2 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-55(S)-3-(N′-(Heptanoyl)-L- Heptanoic acid (S)-3-(L-alaninyl)amino-2,3- C-B449.0 alaninyl)amino-2,3-dihydro-1- (Aldrich)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-56(S)-3-(N′-(3-(4- 3-(4- (S)-3-(L-alaninyl)amino-2,3- C-B 483.2Methylphenyl)propionyl)-L- Methylphenyl)propionicdihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Lancaster) (Example8-B) benzodiazepin-2-one 8C-57 (S)-3-(N′-(3-(4- 3-(4-(S)-3-(L-alaninyl)amino-2,3- C-B 503.0 Chlorophenyl)propionyl)-L-Chlorophenyl)propionic dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- acid 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Trans World) (Example 8-B) benzodiazepin-2-one8C-58 (S)-3-(N′-(3-Phenylbutyryl)-L- 3-Phenylbutyric acid(S)-3-(L-alaninyl)amino-2,3- C-B 483.2 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-59(S)-3-(N′-(4-(4- 4-(4-Methoxyphenyl)butyric (S)-3-(L-alaninyl)amino-2,3-C-B 513.2 Methoxyphenyl)butyryl)-L- acid dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-60(S)-3-(N′-(3- mono-Methyl succinate (S)-3-(L-alaninyl)amino-2,3- C-B451.0 Methoxycarbonylpropionyl)-L- (3- dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- Methoxycarbonylpropionic1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- acid) (Example 8-B)benzodiazepin-2-one (Aldrich) 8C-61 (S)-3-(N′-(4-Phenylbutyryl)-L-4-Phenylbutyric acid (S)-3-(L-alaninyl)amino-2,3- C-B 483.2alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1Hmethyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-62 (S)-3-(N′-(3- 3-(Benzylthio)propionic(S)-3-(L-alaninyl)amino-2,3- C-B 515.2 (Benzylthio)propionyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-(Sigma-Aldrich Rare 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-Chemicals) (Example 8-B) benzodiazepin-2-one 8C-63(S)-3-(N′-(3-Methylpentanoyl)-L- 3-Methylpentanoic acid(S)-3-(L-alaninyl)amino-2,3- C-B 435.2 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-64(S)-3-(N′-(6- Suberic acid monomethyl (S)-3-(L-alaninyl)amino-2,3- C-B507.0 Methoxycarbonylheptanoyl)-L- ester(6-dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-Methoxycarbonylheptanoic 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4-acid) (Example 8-B) benzodiazepin-2-one 8C-65(S)-3-(N′-(2-Indanylacetyl)-L- 2-Indanylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-B 495.0 alaninyl)amino-2,3-dihydro-1-(Lancaster) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-66(S)-3-(N′-(4- 4-Methoxyphenylacetic acid (S)-3-(L-alaninyl)amino-2,3-C-C 485.2 Methoxyphenylacetyl)-L- (Aldrich) dihydro-1-methyl-S-phenyl-1H- alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-67(S)-3-(N′-(o- o-Chlorophenoxyacetic acid (S)-3-(L-alaninyl)amino-2,3-C-C 505.0 Chlorophenoxyacetyl-L- (Lancaster)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-68 (S)-3-(N′-(2-Thiopheneacetyl)-L-2-Thiopheneacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 461.0alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-69 (S)-3-(N′-(3- 3- (S)-3-(L-alaninyl)amino-2,3- C-C523.0 (Trifluoromethyl)phenylacetyl) (Trifluoromethyl)phenyl-dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1- aceticacid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Marshallton)(Example 8-B) benzodiazepin-2-one 8C-70 (S)-3-(N′-(p-Tolylacetyl)-L-p-Tolylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 469.0alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-71 (S)-3-(N′-(2,6- 2,6-Difluoromandelic acid(S)-3-(L-alaninyl)amino-2,3- C-D 448.0 Difluoromandelyl)-1- (Fluorochem)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-72 (S)-3-(N′-(-(4- 3-(4-(S)-3-(L-alaninyl)amino-2,3- C-C 499.0 Methoxyphenyl)propionyly-L-Methoxyphenyl)propionic dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- acid 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B) benzodiazepin-2-one8C-73 (S)-3-(N′-(3,5- 3,5-Difluorophenylacetic(S)-3-(L-alaninyl)amino-2,3- C-C 491.0 Difluorophenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Aldrich)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-74 (S)-3-(N′-(m-Tolylacetyl)-L- m-Tolylaceticacid (S)-3-(L-alaninyl)amino-2,3- C-C 469.0alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-75 (S)-3-(N′-(3-Fluorophenylacetyl)-3-Fluorophenylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 473.0L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-76 (S)-3-(N′-(4- 4-Chlorophenoxyacetic acid(S)-3-(L-alaninyl)amino-2,3 C-C 505.0 Chlorophenoxyacetyl-L- (GrandIsland Biological dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- Company) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-82(S)-3-(N′-(4- 4-Isopropylphenoxyacetic (S)-3-(L-alaninyl)amino-2,3- C-C513.2 Isopropylphenoxyacetyl-L- acid dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- (Lancaster) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-83(S)-3-(N′-(4- 4-Phenoxyphenylacetic acid (S)-3-(L-alaninyl)amino-2,3-C-C 547.0 Phenoxyphenylacetyl)-L- (Trans World)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-84 (S)-3-(N′- Phenylmercaptoacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 487.2 (Phenylmercaptoacetyl)-L-(Aldrich) dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-85 (S)-3-(N′-(4- 4-Ethoxyphenylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 499.0 Ethoxyphenylacetyl)-L- (Aldrich)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-86 (S)-3-(N′-(2,5- 2,5-Dimethoxyphenylacetic(S)-3-(L-alaninyl)amino-2,3- C-C 515.0 Dimethoxyphenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Aldrich)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-87 (S)-3-(N′-(o-Tolylacetyl)-L- o-Tolylaceticacid (S)-3-(L-alaninyl)amino-2,3 C-C 469.0 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-88(S)-3-(N′-(3,3- 3,3-Diphenylpropionic acid (S)-3-(L-alaninyl)amino-2,3-C-C 545.3 Diphenylpropionyl)-L- (Aldrich) dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-89(S)-3-(N′-(3-Phenoxypropionyl)- 3-Phenoxypropionic acid(S)-3-(L-alaninyl)amino-2,3- C-C 485.4 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-90(S)-3-(N′-(Indole-3-acetyl)-L- Indole-3-acetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 494.0 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-91(S)-3-(N′-(4- 4- (S)-3-(L-alaninyl)amino-2,3- C-C 523.0(Trifluoromethyl)phenylacetyl)- (Trifluoromethyl)phenyl-dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1- aceticacid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Maybridge)(Example 8-B) benzodiazepin-2-one 8C-92 (S)-3-(N′-(3,5- 3,5-(S)-3-(L-alaninyl)amino-2,3- C-C 591.0Bis(trifluoromethyl)phenylacetyl)- Bis(trifluoromethyl)phenyl-dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro- acetic acid1,4-benzodiazepin-2-one 1-methyl-5-phenyl-1H-1,4- (Aldrich) (Example8-B) benzodiazepin-2-one 8C-93 (S)-3-(N′-(2- 2-Phenoxyphenylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 547.0 Phenoxyphenylacetyl)-L- (TransWorld) dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-94 (S)-3-(N′-(3- 3-Phenoxyphenylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-D 547.0 Phenoxyphenylacetyl)-L- (Aldrich)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-95 (S)-3-(N′-(4- 4-Fluorophenoxyacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 489.2 Fluorophenoxyacetyl-L- (Aldrich)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-96 (S)-3-(N′-(2,4- 2,4-Dichlorophenylacetic(S)-3-(L-alaninyl)amino-2,3- C-C 523.0 Dichlorophenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Fairfield)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-97 (S)-3-(N′-((Methylthio)acetyl)-L-(Methylthio)acetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 425.0alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-98 (S)-3-(N′-(4-Fluoromandelyl)-L- 4-Fluoromandelicacid (S)-3-(L-alaninyl)amino-2,3- C-D 489.0alaninyl)amino-2,3-dihydro-1- (Lancaster) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-99 (S)-3-(N′-(4- 4-Thionaphthenacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 511.2 Thionaphthenacetyl)-L- (Aldrich)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-100 (S)-3-(N′-(Methoxyacetyl-L- Methoxyaceticacid (S)-3-(L-alaninyl)amino-2,3- C-C 409.0alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-101 (S)-3-(N′-(Ethoxyacetyl-L- Ethoxyacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 422.8 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-102(S)-3-(N′-(3-Indolepropionyl)-L- 3-Indolepropionic acid(S)-3-(L-alaninyl)amino-2,3- C-C 508.2 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-103(S)-3-(N′-(3-(2- 3-(2- (S)-3-(L-alaninyl)amino-2,3- C-C 503.0Chlorophenyl)propionyl)-L- Chlorophenyl)propionicdihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Trans World) (Example8-B) benzodiazepin-2-one 8C-104 (S)-3-(N′-(Butyryl)-L- Butyric acid(S)-3-(L-alaninyl)amino-2,3- C-C 407.2 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-105(S)-3-(N′-(Hexanoyl)-L- Hexanoic acid (S)-3-(L-alaninyl)amino-2,3- C-C435.0 alaninyl)amino-2,3-dihydro-1- (Aldrich)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-106(S)-3-(N′-(5-Phenylpentanoyl)-L- 5-Phenylvaleric acid(S)-3-(L-alaninyl)amino-2,3- C-C 497.0 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-107(S)-3-(N′-(4-(2-Thienyl)butyryl)- 4-(2-Thienyl)butyric acid(S)-3-(L-alaninyl)amino-2,3- C-C 489.2 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-108(S)-3-(N′-(4- 4-Nitrophenoxyacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C516.2 Nitrophenoxyacetyl-L- (Apin) dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-109(S)-3-(N′-(3-(3- 3-(3- (S)-3-(L-alaninyl)amino-2,3- C-C 499.0Methoxyphenyl)propionyl)-L- Methoxyphenyl)propionicdihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Lancaster) (Example8-B) benzodiazepin-2-one 8C-110 (S)-3-(N′-(5-Methylhexanoyl)-L-5-Methylhexanoic acid (S)-3-(L-alaninyl)amino-2,3- C-C 449.0alaninyl)amino-2,3-dihydro-1- (Pfalz and Bauer)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-111(S)-3-(N′-( Hydrocinnamyl-L- Hydrocinnamic acid(S)-3-(L-alaninyl)amino-2,3- C-C 469.0 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-112(S)-3-(N′-(Octanoyl)-L- Octanoic acid (S)-3-(L-alaninyl)amino-2,3- C-C463.2 alaninyl)amino-2,3-dihydro-1- (Aldrich)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-113(S)-3-(N′-(3-(3- 3-(3- (S)-3-(L-alaninyl)amino-2,3- C-D 485.2Hydroxyphenyl)propionyl)-L- Hydroxyphenyl)propionicdihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Lancaster) (Example8-B) benzodiazepin-2-one 8C-114 (S)-3-(N′-(3-(4- 3-(4-(S)-3-(L-alaninyl)amino-2,3- C-D 485.2 Hydroxyphenyl)propionyl)-L-Hydroxyphenyl)propionic dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- acid 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B) benzodiazepin-2-one8C-115 (S)-3-(N′-(3,4,5- 3,4,5-Trifluorophenylacetic(S)-3-(L-alaninyl)amino-2,3- C-C 509.0 Trifluorophenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Fluorochem)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-116 (S)-3-(N′-(5-Hydantoinacetyl)-L-5-Hydantoinacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 477.0alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-117 (S)-3-(N′-(Cyclopentylacetyl)-L- Cyclopentylaceticacid (S)-3-(L-alaninyl)amino-2,3- C-C 447.0alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-118 (S)-3-(N′-(3- 3-(Trifluoromethyl)butyric(S)-3-(L-alaninyl)amino-2,3- C-C 475.0 (Trifluoromethyl)butyryl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Fluorochem)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-119 (S)-3-(N′-(2-Methyl-3- 2-Methyl-3-(S)-3-(L-alaninyl)amino-2,3- C-C 509.2 Benzofuranacetyl)-L-Benzofuranacetic acid dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- (Maybridge) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-120(S)-3-(N′-(Propionyl)-L- Propionic acid (S)-3-(L-alaninyl)amino-2,3- C-C393.0 alaninyl)amino-2,3-dihydro-1- (Aldrich)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-121(S)-3-(N′-(Cyclopropylacetyl)-L- Cyclopropylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 419.0 alaninyl)amino-2,3-dihydro-1-(Lancaster) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-122(S)-3-(N′-(3-Methoxypropionyl)- 3-Methoxypropionic acid(S)-3-(L-alaninyl)amino-2,3- C-C 423.2 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-123(S)-3-(N′-(5-(Thienyl)pentanoyl)- 5-(Thienyl)pentanoic acid(S)-3-(L-alaninyl)amino-2,3- C-C 503.0 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-l H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-124(S)-3-(N′-(3-(4- 3-(4- (S)-3-(L-alaninyl)amino-2,3- C-C 487.2Fluorophenyl)propionyl)-L- Fluorophenyl)propionic aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (TransWorld) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-125 (S)-3-(N′-(3-(4- 3-(4-(S)-3-(L-alaninyl)amino-2,3- C-C 503.0 Fluorophenoxy)propionyl)-L-Fluorophenoxy)propionic dihydro-1-methyl-5-phenyl-1Halaninyl)amino-2,3-dihydro-1- acid 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Maybridge) (Example 8-B) benzodiazepin-2-one8C-126 (S)-3-(N′-(2-Norbornaneacetyl)- 2-Norbornaneacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 473.0 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-128(S)-3-(N′-(2,3- 2,3-Difluoromandelic acid (S)-3-(L-alaninyl)amino-2,3-C-C 507.0 Difluoromandelyl)-L- (Fluorochem)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-129 (S)-3-(N -(3-Pentenoyl)-L- 3-Pentenoic acid(S)-3-(L-alaninyl)amino-2,3- C-C 419.0 alaninyl)amino-2,3-dihydro-1-(Fluka) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-130(S)-3-(N′-(4-(2,4- 4-(2,4- (S)-3-(L-alaninyl)amino-2,3- C-C 567.2dichlorophenoxy)butyryl)-L- dichlorophenoxy)butyricdihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B)benzodiazepin-2-one 8C-131 (S)-3-(N′-(2,3- 2,3-Dichlorophenoxyacetic(S)-3-(L-alaninyl)amino-2,3- C-C 539.2 Dichlorophenoxyacetyl-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Aldrich)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-133 (S)-3-(N′-(2-Fluorophenylacetyl)-2-Fluorophenylacetic acid (S)-3-(L-alaninyl)amino-2,3 C-C 473.0L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-135 (S)-3-(N′-(2-Nitrophenylacetyl)-2-Nitrophenylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 499.8L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1Hmethyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-136 (S)-3-(N′-(4- 4- (S)-3-(L-alaninyl)amino-2,3- C-C501.0 (Hydroxymethyl)phenoxyacetyl) (Hydroxymethyl)phenoxy-dihydro-1-methyl-5-phenyl-1H- L-alaninyl)amino-2,3-dihydro-1- aceticacid 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Sigma) (Example8-B) benzodiazepin-2-one 8C-137 (S)-3-(N′-(2-Fluoro-3- 2-Fluoro-3-(S)-3-(L-alaninyl)amino-2,3- C-C 541.0 (trifluoromethyl)Phenylacetyl)-L-(trifluoromethyl)phenyl- dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- acetic acid 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Fluorochem) (Example 8-B) benzodiazepin-2-one8C-138 (S)-3-(N′-(2,4,6- 2,4,6-Trifluorophenylacetic(S)-3-(L-alaninyl)amino-2,3- C-C 509.0 Trifluorophenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Fluorochem)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-139 (S)-3-(N′-(4-Fluoro-2- 4-Fluoro-2-(S)-3-(L-alaninyl)amino-2,3- C-C 541.0 (trifluoromethyl)phenylacetyl)-L-(trifluoromethyl)phenyl- dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- acetic acid 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Fluorochem) (Example 8-B) benzodiazepin-2-one8C-140 (S)-3-(N′-(4,4,4- 4,4,4-Trifluorobutyric acid(S)-3-(L-alaninyl)amino-2,3- C-C 461.0 Trifluorobutyryl)-L- (Fluorochem)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-141 (S)-3-(N′-(2-Fluoro-4- 2-Fluoro-4-(S)-3-(L-alaninyl)amino-2,3 C-C 541.0 (trifluoromethyl)phenylacetyl)-L-(trifluoromethyl)phenyl- dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- acetic acid 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Fluorochem) (Example 8-B) benzodiazepin-2-one8C-142 (S)-3-(N′-(4-Bromophenylacetyl)- 4-Bromophenylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 533.0 L-alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-143(S)-3-(N′-(3-(4- 3-(4- (S)-3-(L-alaninyl)amino-2,3- C-C 515.0Fluorobenzoyl)propionyl)-L- Fluorobenzoyl)propionicdihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B)benzodiazepin-2-one 8C-144 (S)-3-(N′-((2-(2-Methylphenoxy)acetic(S)-3-(L-alaninyl)amino-2,3- C-C 485.2 Methylphenoxy)acetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Lancaster)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-145 (S)-3-(N′-(4- 4-Methoxyphenoxyacetic(S)-3-(L-alaninyl)amino-2,3- C-C 501.0 Methoxyphenoxyacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Lancaster)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-146 (S)-3-(N′-(3- 3-(Phenylsulfonyl)propionic(S)-3-(L-alaninyl)amino-2,3- C-C 531 (Phenylsulfonyl)propionyl)-L- aciddihydro-1-methyl-5-phenyl-1H- (M-1) alaninyl)amino-2,3-dihydro-1-(Aldrich) 1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-147 (S)-3-(N′-(2- 2-Methoxyphenylacetic acid(S)-3-(L-alaninyl)amino-2,3- C-C 485.2 Methoxyphenylacetyl)-L- (Aldrich)dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-148 (S)-3-(N′-(2-Bromophenylacetyl)-2-Bromophenylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 535.0L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-149 (S)-3-(N′-(p-Isopropyl p-Isopropyl phenylacetic(S)-3-(L-alaninyl)amino-2,3- C-C 497.0 phenylacetyl)-L-alaninyl)amino-acid dihydro-1-methyl-5-phenyl-1H- 2,3-dihydro-1-methyl-5-phenyl-(Lancaster) 1,4-benzodiazepin-2-one 1H-1,4-benzodiazepin-2-one (Example8-B) 8C-150 (S)-3-(N′-(4-Pentenoyl)-L- 4-Pentenoic acid(S)-3-(L-alaninyl)amino-2,3- C-C 419.0 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-151(S)-3-(N′-(4- 4-Hydroxyphenoxyacetic (S)-3-(L-alaninyl)amino-2,3- C-D487.2 Hydroxyphenoxyacetyl-L- acid dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- (Acros) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-152(S)-3-(N′-(4-oxopentanoyl)-L- Levulinic acid(S)-3-(L-alaninyl)amino-2,3- C-C 433.1 alaninyl)amino-2,3-dihydro-1-(4-Oxopentanoic acid) dihydro-1-methyl-5-phenyl-1H- (M-1)methyl-5-phenyl-1H-1,4- (Aldrich) 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example 8-B) 8C-153 (S)-3-(N′-(2-2-Hydroxyphenylacetic acid (S)-3-(L-alaninyl)amino-2,3- C-D 471.0Hydroxyphenylacetyl)-L- (Aldrich) dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-154(S)-3-(N′-(3,4- 3,4-Dimethoxyphenylacetic (S)-3-(L-alaninyl)amino-2,3-C-C 515.0 Dimethoxyphenylacetyl)-L- acid dihydro-1-methyl-5-phenyl-1H-alaninyl)amino-2,3-dihydro-1- (Aldrich) 1,4-benzodiazepin-2-onemethyl-5-phenyl-1H-1,4- (Example 8-B) benzodiazepin-2-one 8C-155(S)-3-(N′-(3-(4- 3-(4- (S)-3-(L-alaninyl)amino-2,3- C-C 527.0Methoxybenzoyl)Propionyl)-L- Methoxybenzoyl)Propionicdihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B)benzodiazepin-2-one 8C-156 (S)-3-(N′-(Thiophene-3-acetyl)-Thiophene-3-acetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 461.0L-alaninyl)amino-2,3-dihydro-1- (Acros) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-157 (S)-3-(N′-(6-Phenylhexanoyl)-L- 6-Phenylhexanoicacid (S)-3-(L-alaninyl)amino-2,3 C-C 511.2 alaninyl)amino-2,3-dihydro-1-(Avocado) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-158(S)-3-(N′-(Isovaleryl)-L- Isovaleric acid (S)-3-(L-alaninyl)amino-2,3-C-C 420.8 alaninyl)amino-2,3-dihydro-1- (Aldrich)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-159(S)-3-(N′-(2,3,5- 2,3,5-Trifluorophenylacetic(S)-3-(L-alaninyl)amino-2,3- C-C 508.8 Trifluorophenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Fluorochem)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-160 (S)-3-(N′-(2,4,5- 2,4,5-Trifluorophenylacetic(S)-3-(L-alaninyl)amino-2,3- C-C 509.0 Trifluorophenylacetyl)-L- aciddihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- (Fluorochem)1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-161 (S)-3-(N′-(1-Adamantaneacetyl)-1-Adamantaneacetic acid (S)-3-(L-alaninyl)amino-2,3- C-C 513.2L-alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-162 (S)-3-(N′- Cyclohexanepentanoic acid(S)-3-(L-alaninyl)amino-2,3 C-C 503.0 (Cyclohexanepentanoyl)-L-(Aldrich) dihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1-1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Example 8-B)benzodiazepin-2-one 8C-163 (S)-3-(N′-(2-Thiopheneacetyl)-L-2-Thiopheneacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 523 .0phenylglycinyl)amino-2,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-AA) 8C-164 (S)-3-(N′-(3- 3-(S)-3-(L-phenylglycinyl)amino- C-C 585.0 (Trifluoromethyl)Phenylacetyl)-(Trifluoromethyl)phenyl- 2,3-dihydro-1-methyl-5-phenyl-L-phenylglycinyl)amino-2,3 acetic acid 1H-1,4-benzodiazepin-2-onedihydro-1-methyl-5-phenyl-1H- (Marshallton) (Example C-AA)1,4-benzodiazepin-2-one 8C-165 (S)-3-(N′-(3,5- 3,5-Difluorophenylacetic(S)-3-(L-phenylglycinyl)amino- C-C 553.0 Difluorophenylacetyl)-L- acid2,3-dihydro-1-methyl-5-phenyl- phenylglycinyl)amino-2,3- (Aldrich)1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H- (Example C-AA)1,4-benzodiazepin-2-one 8C-166 (S)-3-(N′-(m-Tolylacetyl)-L-m-Tolylacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 531.2phenylglycinyl)amino-2,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-AA) 8C-167(S)-3-(N′-(3-Fluorophenylacetyl)- 3-Fluorophenylacetic acid(S)-3-(L-phenylglycinyl)amino- C-C 535.2 L-phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-168(S)-3-(N′-(3-Bromophenylacetyl)- 3-Bromophenylacetic acid(S)-3-(L-phenylglycinyl)amino- C-C 595.2 L-phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-169(S)-3-(N′-(3-Chlorophenylacetyl)- 3-Chlorophenylacetic acid(S)-3-(L-phenylglycinyl)amino- C-C 551.2 L-phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-170(S)-3-(N′-(3,4- 3,4- (S)-3-(L-phenylglycinyl)amino- C-C 561.2Methylenedioxyphenylacetyl)-L- Methylenedioxyphenylacetic2,3-dihydro-1-methyl-5-phenyl- phenylglycinyl)amino-2,3- acid1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H- (Aldrich)(Example C-AA) 1,4-benzodiazepin-2-one 8C-171 (S)-3-(N′-Phenylmercaptoacetic acid (S)-3-(L-phenylglycinyl)amino- C-C 549.0(Phenylmercaptoacetyl)-L- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-phenylglycinyl)amino-2,3- 1H-1,4-benzodiazepin-2-onedihydro-1-methyl-5-phenyl-1H- (Example C-AA) 1,4-benzodiazepin-2-one8C-173 (S)-3-(N′-(3,5- 3,5- (S)-3-(L-phenylglycinyl)amino- C-C 653.0Bis(trifluoromethyl)phenylacetyl)- Bis(trifluoromethyl)phenyl-2,3-dihydro-1-methyl-5-phenyl- 1-phenylglycinyl)amino-2,3- acetic acid1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H- (Aldrich)(Example C-AA) 1,4-benzodiazepin-2-one 8C-174(S)-3-(N′-((Methylthio)acetyl)-L- (Methylthio)acetic acid(S)-3-(L-phenylglycinyl)amino- C-C 487.2 phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-175(S)-3-(N′-(Phenoxyacetyl-L- Phenoxyacetic acid(S)-3-(L-phenylglycinyl)amino- C-C 533.0 phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-176(S)-3-(N′-(Phenylacetyl)-L- Phenylacetic acid(S)-3-(L-phenylglycinyl)amino- C-C 517.2 phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-177(S)-3-(N′-(Cyclohexylacetyl)-L- Cyclohexylacetic acid(S)-3-(L-phenylglycinyl)amino- C-C 523.2 phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-178(S)-3-(N′-(2,5- 2,5-Difluorophenylacetic (S)-3-(L-phenylglycinyl)amino-C-C 553.0 Difluorophenylacetyl)-L- acid 2,3-dihydro-1-methyl-5-phenyl-phenylglycinyl)amino-2,3- (Aldrich) 1H-1,4-benzodiazepin-2-onedihydro-1-methyl-5-phenyl-1H- (Example C-AA) 1,4-benzodiazepin-2-one8C-179 (S)-3-(N′-(Benzo[b]thiophene-3- Benzo[b]thiophene-3-(S)-3-(L-phenylglycinyl)amino- C-C 573.2 acetyl)-L-phenylglycinyl)amino-acetic acid 2,3-dihydro-1-methyl-5-phenyl-2,3-dihydro-1-methyl-5-phenyl- (Aldrich) 1H-1,4-benzodiazepin-2-one1H-1,4-benzodiazepin-2-one (Example C-AA) 8C-180(S)-3-(N′-(benzoylformyl)-1- Benzoylformic acid(S)-3-(L-phenylglycinyl)amino- C-C 531.2 phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-181(S)-3-(N′-(2,6- 2,6-Difluorophenylacetic (S)-3-(L-phenylglycinyl)amino-C-C 553.0 Difluorophenylacetyl)-L- acid 2,3-dihydro-1-methyl-5-phenyl-phenylglycinyl)amino-2,3- (Aldrich) 1H-1,4-benzodiazepin-2-onedihydro-1-methyl-5-phenyl-1H- (Example C-AA) 1,4-benzodiazepin-2-one8C-182 (S)-3-(N′-(2,4- 2,4-Difluorophenylacetic(S)-3-(L-phenylglycinyl)amino- C-C 553.0 Difluorophenylacetyl)-L- acid2,3-dihydro-1-methyl-5-phenyl- phenylglycinyl)amino-2,3- (Aldrich)1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H- (Example C-AA)1,4-benzodiazepin-2-one 8C-183 (S)-3-(N′-(3,4- 3,4-Difluorophenylacetic(S)-3-(L-phenylglycinyl)amino- C-C 553.0 Difluorophenylacetyl)-L- acid2,3-dihydro-1-methyl-5-phenyl- phenylglycinyl)amino-2,3- (Aldrich)1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H- (Example C-AA)1,4-benzodiazepin-2-one 8C-184 (S)-3-(N′-(Butyryl-L- Butyric acid(S)-3-(L-phenylglycinyl)amino- C-C 469.0 phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-185(S)-3-(N′-(Heptanoyl)-L- Heptanoic acid (S)-3-(L-phenylglycinyl)amino-C-C 511.2 phenylglycinyl)amino-2,3- (Aldrich)2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-186(S)-3-(N′-(4-(2-Thienyl)butyryl)- 4-(2-Thienyl)butyric acid(S)-3-(L-phenylglycinyl)amino- C-C 551.0 L-phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-187(S)-3-(N′-(5-Methylhexanoyl)-L- 5-Methylhexanoic acid(S)-3-(L-phenylglycinyl)amino- C-C 511.2 phenylglycinyl)amino-2,3-(Pfaltz and Bauer) 2,3-dihydro-1-methyl-5-phenyl-dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-AA) 8C-188(S)-3-(N′-(Hydrocinnamyl)-L- Hydrocinnamic acid(S)-3-(L-phenylglycinyl)amino- C-C 531.2 phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-189(S)-3-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid(S)-3-(L-phenylglycinyl)amino- C-C 509.2 phenylglycinyl)amino-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-190(S)-3-(N′-(Propionyl)-L- Propionic acid (S)-3-(L-phenylglycinyl)amino-C-C 455.0 phenylglycinyl)amino-2,3- (Aldrich)2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-AA) 8C-191(S)-3-(N′-(3,4,5- 3,4,5-Trifluorophenylacetic(S)-3-(L-phenylglycinyl)amino- C-C 571.0 Trifluorophenylacetyl)-L- acid2,3-dihydro-1-methyl-5-phenyl- phenylglycinyl)amino-2,3- (Fluorochem)1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H- (Example C-AA)1,4-benzodiazepin-2-one 8C-192 (S)-3-(N′-(4-Phenylbutyryl)-L-4-Phenylbutyric acid (S)-3-(L-phenylglycinyl)amino- C-C 545.2phenylglycinyl)amino-2,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-AA) 8C-1933-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid3-(L-alaninyl)amino-2,3- C-E 557.2 alaninyl)amino-2,3-dihydro-5-(Aldrich) dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobutyl)-trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-AC) 8C-194 3-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneaceticacid 3-(L-alaninyl)amino-1-(2-oxo-2- C-E 565.2alaninyl)amino-1-(2-oxo-2- (Aldrich) phenylethyl)-2,3-dihydro-5-phenylethyl)-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-phenyl-1H-1,4-benzodiazepin-2- one one (Example C-AB) 8C-1953-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid3-(L-alaninyl)amino-1-methyl- C-E 468.1 alaninyl)amino-1-methyl-2,3-(Aldrich) 2,3-dihydro-5-(2-thiazolyl)-1H dihydro-5-(2-thiazolyl)-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-1963-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid3-(L-alaninyl)amino-7-chloro- C-E 495.1 alaninyl)amino-7-chloro-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C) 8C-1973-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid3-(L-alaninyl)amino-7-chloro-5- C-E 529.1 alaninyl)amino-7-chloro-5-(2-(Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 531.1chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-1983-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid3-(L-alaninyl)amino-5-(2- C-B 467.1 alaninyl)amino-5-(2-thienyl)-2,3-(Aldrich) thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI) 8C-1993-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid3-(L-alaninyl)amino-5- C-B 467.2 alaninyl)amino-5-cyclohexyl-2,3-(Aldrich) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-200 3-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid3-(L-alaninyl)amino-7-bromo-5- C-B 557.1 alaninyl)amino-7-bromo-5-(2-(Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 559.1fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-2013-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid3-(L-alaninyl)-amino-)-2,4- C-B 527.3 alaninyl)-amino-)-2,4-dioxo-1,5-(Aldrich) dioxo-1,5-bis-(2,2- bis-(2,2-dimethylpropyl)-2,3,4,5-dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepine benzodiazepine (Example 8-V) 8C-2023-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-2,3- C-E 587.2 L-alaninyl)amino-2,3-dihydro-5- aciddihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobutyl)- (Aldrich)trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-AC) 8C-203 3-(N′-(3,5-Difluorophenylacetyl)-3,5-Difluorophenylacetic 3-(L-alaninyl)amino-1-(2-oxo-2- C-B 595.2L-alaninyl)amino-1-(2-oxo-2- acid phenylethyl)-2,3-dihydro-5-phenylethyl)-2,3-dihydro-5- (Aldrich) phenyl-1H-1,4-benzodiazepin-2-phenyl-1H-1,4-benzodiazepin-2- one one (Example C-AB) 8C-2043-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-1-methyl- C-B 498.1 L-alaninyl)amino-1-methyl-2,3-acid 2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-(Aldrich) 1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH)8C-205 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-7-chloro- C-E 525.2 L-alaninyl)amino-7-chloro-2,3-acid 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-(Aldrich) 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example8-C) 8C-206 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-7-chloro-5- C-B 559.1L-alaninyl)amino-7-chloro-5-(2- acid (2-chlorophenyl)-2,3-dihydro-1-561.1 chlorophenyl)-2,3-dihydro-1- (Aldrich)methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2- one one(Example 8-F) 8C-207 3-(N′-(3,5-Difluorophenylacetyl)-3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-(2- C-B 497.1L-alaninyl)amino-5-(2-thienyl)- acid thienyl)-2,3-dihydro-1-methyl-2,3-dihydro-1-methyl-1H-1,4- (Aldrich) 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AI) 8C-2083-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5- C-B 497.2 L-alaninyl)amino-5-cyclohexyl- acidcyclohexyl-2,3-dihydro-1- 2,3-dihydro-1-methyl-1H-1,4- (Aldrich)methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-209 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-7-bromo-5- C-B 587.1 L-alaninyl)amino-7-bromo-5-(2-acid (2-fluorophenyl)-2,3-dihydro-1- 590.1 fluorophenyl)-2,3-dihydro-1-(Aldrich) methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2-one one (Example 8-D) 8C-210 3-(-(3,5- 3,5-Difluorophenylacetic3-(L-alaninyl)-amino-)-2,4- C-B 557.3 Difluorophenylacetyl)-L- aciddioxo-1,5-bis-(2,2- alaninyl)-amino-)-2,4-dioxo-1,5- (Aldrich)dimethylpropyl)-2,3,4,5- bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine(Example 8-V) 8C-211 3-(N′-(3-Fluorophenylacetyl)-L-3-Fluorophenylacetic acid 3-(L-alaninyl)amino-2,3- C-E 569.2alaninyl)amino-2,3-dihydro-5- (Aldrich) dihydro-5-phenyl-1-(4,4,4-phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC) 8C-2123-(N′-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid3-(L-alaninyl)amino-1-(2-oxo-2- C-E 577.2 alaninyl)amino-1-(2-oxo-2-(Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2- one one(Example C-AB) 8C-213 3-(N′-(3-Fluorophenylacetyl)-L-3-Fluorophenylacetic acid 3-(L-alaninyl)amino-1-methyl- C-E 480.1alaninyl)amino-1-methyl-2,3- (Aldrich) 2,3-dihydro-5-(2-thiazolyl)-1H-dihydro-5-(2-thiazolyl)-1H-1,4- 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AH) 8C-2143-(N′-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid3-(L-alaninyl)amino-7-chloro- C-E 507.2 alaninyl)amino-7-chloro-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C) 8C-2153-(N′-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid3-(L-alaninyl)amino-7-chloro-5- C-E 541.1 alaninyl)amino-7-chloro-5-(2-(Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 543.1chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-2163-(N′-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid3-(L-alaninyl)amino-5-(2- C-E 479.1 alaninyl)amino-5-(2-thienyl)-2,3-(Aldrich) thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI) 8C-2173-(N′-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid3-(L-alaninyl)amino-5- C-E 479.2 alaninyl)amino-5-cyclohexyl-2,3-(Aldrich) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-218 3-(N′-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid3-(L-alaninyl)amino-7-bromo-5- C-E 571.1 alaninyl)amino-7-bromo-5-(2-(Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 573.1fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-219 3-(N′-(3-Fluorophenylacetyl)-L- 3-Fluorophenylacetic acid3-(L-alaninyl)-amino-)-2,4- C-E 539.3 alaninyl)-amino-)-2,4-dioxo-1,5-(Aldrich) dioxo-1,5-bis-(2,2- bis-(2,2-dimethylpropyl)-2,3,4,5-dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepine benzodiazepine (Example 8-V) 8C-2203-(N′-(Methylthio)acetyl)-L- (Methylthio)acetic acid3-(L-alaninyl)amino-2,3- C-E 521.2 alaninyl)amino-2,3-dihydro-5-(Aldrich) dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobutyl)-trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-AC) 8C-221 3-(N′-(Methylthio)acetyl)-L- (Methylthio)aceticacid 3-(L-alaninyl)amino-1-(2-oxo-2- C-E 529.2alaninyl)amino-1-(2-oxo-2- (Aldrich) phenylethyl)-2,3-dihydro-5-phenylethyl)-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-phenyl-1H-1,4-benzodiazepin-2- one one (Example C-AB) 8C-2223-(N′-(Methylthio)acetyl)-L- (Methylthio)acetic acid3-(L-alaninyl)amino-1-methyl- C-E 432.1 alaninyl)amino-1-methyl-2,3-(Aldrich) 2,3-dihydro-5-(2-thiazolyl)-1H-dihydro-5-(2-thiazolyl)-1H-1,4- 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AH) 8C-223 3-(N′-(Methylthio)acetyl)-L-(Methylthio)acetic acid 3-(L-alaninyl)amino-7-chloro- C-E 459.1alaninyl)amino-7-chloro-2,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example 8-C) 8C-2243-(N′-(Methylthio)acetyl)-L- (Methylthio)acetic acid3-(L-alaninyl)amino-7-chloro-5- C-E 493.1 alaninyl)amino-7-chloro-5-(2-(Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 495.1chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-2253-(N′-(Methylthio)acetyl)-L- (Methylthio)acetic acid3-(L-alaninyl)amino-5-(2- C-B 431.1 alaninyl)amino-5-(2-thienyl)-2,3-(Aldrich) thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI) 8C-2263-(N′-(Methylthio)acetyl)-L- (Methylthio)acetic acid3-(L-alaninyl)amino-5- C-E 431.2 alaninyl)amino-5-cyclohexyl-2,3-(Aldrich) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-227 3-(N′-(Methylthio)acetyl)-L- (Methylthio)acetic acid3-(L-alaninyl)amino-7-bromo-5- C-B 521.1 alaninyl)amino-7-bromo-5-(2-(Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 523.1fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-2283-(N′-(Methylthio)acetyl)-L- (Methylthio)acetic acid3-(L-alaninyl)-amino-)-2,4- C-E 491.3 alaninyl)-amino-)-2,4-dioxo-1,5-(Aldrich) dioxo-1,5-bis-(2,2- bis-(2,2-dimethylpropyl)-2,3,4,5-dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepine benzodiazepine (Example 8-V) 8C-2293-(N′-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino-2,3- C-E551.2 alaninyl)amino-2,3-dihydro-5- (Aldrich) dihydro-5-phenyl-1-(4,4,4-phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC) 8C-2303-(N′-(Phenylacetyl)-L- Phenylacetic acid3-(L-alaninyl)amino-1-(2-oxo-2- C-E 559.5 alaninyl)amino-1-(2-oxo-2-(Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2- one one(Example C-AB) 8C-231 3-(N′-(Phenylacetyl)-L- Phenylacetic acid3-(L-alaninyl)amino-1-methyl- C-E 462.2 alaninyl)amino-1-methyl-2,3-(Aldrich) 2,3-dihydro-5-(2-thiazolyl)-1H-dihydro-5-(2-thiazolyl)-1H-1,4- 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AH) 8C-232 3-(N′-(Phenylacetyl)-L-Phenylacetic acid 3-(L-alaninyl)amino-7-chloro- C-E 489.2alaninyl)amino-7-chloro-2,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example 8-C) 8C-233 3-(N′-(Phenylacetyl)-L-Phenylacetic acid 3-(L-alaninyl)amino-7-chloro-5- C-E 523.1alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2,3-dihydro-1-525.1 chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-2343-(N′-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino-5-(2- C-E461.1 alaninyl)amino-5-(2-thienyl)-2,3- (Aldrich)thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI) 8C-2353-(N′-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)amino-5- C-B461.2 alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-236 3-(N′-(Phenylacetyl)-L- Phenylacetic acid3-(L-alaninyl)amino-7-bromo-5- C-B 553.1 alaninyl)amino-7-bromo-5-(2-(Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 554.1fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-2373-(N′-(Phenylacetyl)-L- Phenylacetic acid 3-(L-alaninyl)-amino-)2,4- C-E521.3 alaninyl)-amino-)2,4-dioxo-1,5- (Aldrich) dioxo-1,5-bis-(2,2-bis-(2,2-dimethylpropyl)-2,3,4,5- dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine(Example 8-V) 8C-238 3-(N′-(Benzoylformyl)-L- Benzoylformic acid3-(L-alaninyl)amino-2,3- C-E 565.2 alaninyl)amino-2,3-dihydro-5-(Aldrich) dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobutyl)-trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-AC) 8C-239 3-(N′-(Benzoylformyl)-L- Benzoylformic acid3-(L-alaninyl)amino-1-(2-oxo-2- C-E 573.2 alaninyl)amino-1-(2-oxo-2-(Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2- one one(Example C-AB) 8C-240 3-(N′-(Benzoylformyl)-L- Benzoylformic acid3-(L-alaninyl)amino-1-methyl- C-E 476.1 alaninyl)amino-1-methyl-2,3-(Aldrich) 2,3-dihydro-5-(2-thiazolyl)-1H-dihydro-5-(2-thiazolyl)-1H-1,4- 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AH) 8C-241 3-(N′-(Benzoylformyl)-L-Benzoylformic acid 3-(L-alaninyl)amino-7-chloro- C-E 503.1alaninyl)amino-7-chloro-2,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example 8-C) 8C-242 3-(N′-(Benzoylformyl)-L-Benzoylformic acid 3-(L-alaninyl)amino-7-chloro-5- C-E 537.1alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2,3-dihydro-1-539.1 chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-2433-(N′-(Benzoylformyl)-L- Benzoylformic acid 3-(L-alaninyl)amino-5-(2-C-E 475.1 alaninyl)amino-5-(2-thienyl)-2,3- (Aldrich)thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI) 8C-2443-(N -(Benzoylformyl)-L- Benzoylformic acid 3-(L-alaninyl)amino-5- C-E475.2 alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-245 3-(N′-(Benzoylformyl)-L- Benzoylformic acid3-(L-alaninyl)amino-7-bromo-5- C-E 567.1 alaninyl)amino-7-bromo-5-(2-(Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 568.1fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-2463-(N′-(Benzoylformyl)- L-Benzoylformic acid 3-(L-alaninyl)-amino-)-2,4-C-E 535.3 alaninyl)-amino-)-2,4-dioxo-1,5- (Aldrich) dioxo-1,5-bis-(2,2-bis-(2,2-dimethylpropyl)-2,3,4,5- dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine(Example 8-V) 8C-247 3-(N′-(Butyryl-L- Butyric acid3-(L-alaninyl)amino-2,3- C-E 503.2 alaninyl)amino-2,3-dihydro-5-(Aldrich) dihydro-5-phenyl-1-4,4,4- phenyl-1-(4,4,4-trifluorobutyl)-trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-AC) 8C-248 3-(N′-(Butyryl-L- Butyric acid3-(L-alaninyl)amino-1-(2-oxo-2- C-E 511.2 alaninyl)amino-1-(2-oxo-2-(Aldrich) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2- one one(Example C-AB) 8C-249 3-(N′-(Butyryl-L- Butyric acid3-(L-alaninyl)amino-1-methyl- C-E 414.1 alaninyl)amino-1-methyl-2,3-(Aldrich) 2,3-dihydro-5-(2-thiazolyl)-1H-dihydro-5-(2-thiazolyl)-1H-1,4- 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AH) 8C-250 3-(N′-(Butyryl-L- Butyric acid3-(L-alaninyl)amino-7-chloro- C-E 441.2 alaninyl)amino-7-chloro-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C) 8C-2513-(N′-(Butyryl-L- Butyric acid 3-(L-alaninyl)amino-7-chloro-5- C-E 475.1alaninyl)amino-7-chloro-5-(2- (Aldrich) (2-chlorophenyl)-2,3-dihydro-1-477.1 chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-2523-(N′-(Butyryl-L- Butyric acid 3-(L-alaninyl)amino-5-(2- C-E 413.1alaninyl)amino-5-(2-thienyl)-2,3- (Aldrich)thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI) 8C-2533-(N′-(Butyryl-L- Butyric acid 3-(L-alaninyl)amino-5- C-E 413.2alaninyl)amino-5-cyclohexyl-2,3- (Aldrich) cyclohexyl-2,3-dihydro-1-dihydro-1-methyl-1H-1,4- methyl-1H-1,4-benzodiazepin-2-benzodiazepin-2-one one (Example 8-G) 8C-254 3-(N′-(Butyryl-L- Butyricacid 3-(L-alaninyl)amino-7-bromo-5- C-E 503.1alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2,3-dihydro-1-506.1 fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-255 3-(N′-(Butyryl)-L-alaninyl)- Butyric acid 3-(L-alaninyl)-amino-)-2,4- C-E473.3 amino-)-2,4-dioxo-1,5-bis-(2,2- (Aldrich) dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5- dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5-tetrahydro-1H-1,5- benzodiazepine benzodiazepine (Example 8-V) 8C-2563-(N′-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid3-(L-alaninyl)amino-2,3- C-E 585.2 alaninyl)amino-2,3-dihydro-5-(Aldrich) dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobutyl)-trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-AC) 8C-257 3-(N′-(4-(2-Thienyl)butyryl)-L-4-(2-Thienyl)butyric acid 3-(L-alaninyl)amino-1-(2-oxo-2- C-E 593.2alaninyl)amino-1-(2-oxo-2- (Aldrich) phenylethyl)-2,3-dihydro-5-phenylethyl)-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2- phenyl1H-1,4-benzodiazepin-2- one one (Example C-AB) 8C-2583-(N′-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid3-(L-alaninyl)amino-1-methyl- C-E 496.1 alaninyl)amino-1-methyl-2,3-(Aldrich) 2,3-dihydro-5-(2-thiazolyl)-1H-dihydro-5-(2-thiazolyl)-1H-1,4- 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AH) 8C-2593-(N′-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid3-(L-alaninyl)amino-7-chloro- C-E 523.2 alaninyl)amino-7-chloro-2,3-(Aldrich) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C) 8C-2603-(N′-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid3-(L-alaninyl)amino-7-chloro-5- C-E 557.1 alaninyl)amino-7-chloro-5-(2-(Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 559.1chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-2613-(N′-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid3-(L-alaninyl)amino-5-(2- C-E 495.1 alaninyl)amino-5-(2-thienyl)-2,3-(Aldrich) thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AT) 8C-2623-(N′-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid3-(L-alaninyl)amino-5- C-E 495.2 alaninyl)amino-5-cyclohexyl-2,3-(Aldrich) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-263 3-(N-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid3-(L-alaninyl)amino-7-bromo-5 C-E 585.1 alaninyl)amino-7-bromo-5-(2-(Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 587.1fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-2643-(N′-(4-(2-Thienyl)butyryl)-L- 4-(2-Thienyl)butyric acid3-(L-alaninyl)-amino-)-2,4- C-B 555.3 alaninyl)-amino-)-2,4-dioxo-1,5-(Aldrich) dioxo-1,5-bis-(2,2- bis-(2,2-dimethylpropyl)-2,3,4,5-dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepine benzodiazepine (Example 8-V) 8C-2653-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-2,3- C-E 543.3 alaninyl)amino-2,3-dihydro-5-(Aldrich) dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobutyl)-trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-AC) 8C-266 3-(N′-(Cyclopentylacetyl)-L- Cyclopentylaceticacid 3-(L-alaninyl)amino-1-(2-oxo-2- C-E 551.3alaninyl)amino-1-(2-oxo-2- (Aldrich) phenylethyl)-2,3-dihydro-5-phenylethyl)-2,3-dihydro-5- phenyl-1H-1,4-benzodiazepin-2-phenyl-1H-1,4-benzodiazepin-2- one one (Example C-AB) 8C-2673-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-1-methyl- C-E 454.2 alaninyl)amino-1-methyl-2,3-(Aldrich) 2,3-dihydro-5-(2-thiazolyl)-1H-dihydro-5-(2-thiazolyl)-1H-1,4- 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AH) 8C-268 3-(N′-(Cyclopentylacetyl)-L-Cyclopentylacetic acid 3-(L-alaninyl)amino-7-chloro- C-E 481.2alaninyl)amino-7-chloro-2,3- (Aldrich) 2,3-dihydro-1-methyl-5-phenyl-dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example 8-C) 8C-2693-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-7-chloro-5- C-E 515.2 alaninyl)amino-7-chloro-5-(2-(Aldrich) (2-chlorophenyl)-2,3-dihydro-1- 517.2chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-2703-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-(2- C-E 453.1 alaninyl)amino-5-(2-thienyl)-2,3-(Aldrich) thienyl)-2,3-dihydro-1-methyl- dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI) 8C-2713-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5- C-E 453.3 alaninyl)amino-5-cyclohexyl-2,3-(Aldrich) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-272 3-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-7-bromo-5- C-E 543.1 alaninyl)amino-7-bromo-5-(2-(Aldrich) (2-fluorophenyl)-2,3-dihydro-1- 546.1fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-2733-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)-amino-)-2,4- C-E 513.3 alaninyl)-amino-)-2,4-dioxo-1,5-(Aldrich) dioxo-1,5-bis-(2,2- bis-(2,2-dimethylpropyl)-2,3,4,5-dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5-. tetrahydro-1H-1,5-benzodiazepine benzodiazepine (Example 8-F) 8C-274 3-(N′-(3-3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-2,3- C-E 571.2(Trifluoromethyl)butyryl)-L- acid dihydro-5-phenyl-1-(4,4,4-alaninyl)amino-2,3-dihydro-5- (Fluorochem) trifluorobutyl)-1H-1,4-phenyl-1-(4,4,4-trifluorobutyl)- benzodiazepin-2-one1H-1,4-benzodiazepin-2-one (Example C-AC) 8C-275 3-(N′-(3-3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-1-(2-oxo-2- C-B 579.2(Trifluoromethyl)butyryl)-L- acid phenylethyl)-2,3-dihydro-5-alaninyl)amino-1-(2-oxo-2- (Fluorochem) phenyl-1H-1,4-benzodiazepin-2-phenylethyl)-2,3-dihydro-5- one phenyl-1H-1,4-benzodiazepin-2- (ExampleC-AB) one 8C-276 3-(N′-(3- 3-(Trifluoromethyl)butyric3-(L-alaninyl)amino-1-methyl- C-B 482.1 (Trifluoromethyl)butyryl)-L-acid 2,3-dihydro-5-(2-thiazolyl)-1H- alaninyl)amino-1-methyl-2,3-(Fluorochem) 1,4-benzodiazepin-2-one dihydro-5-(2-thiazolyl)-1H-1,4-(Example C-AH) benzodiazepin-2-one 8C-277 3-(N′-(3-3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-7-chloro- C-B 509.1(Trifluoromethyl)butyryl)-L- acid 2,3-dihydro-1-methyl-5-phenyl-alaninyl)amino-7-chloro-2,3- (Fluorochem) 1H-1,4-benzodiazepin-2-onedihydro-1-methyl-5-phenyl-1H- (Example 8-C) 1,4-benzodiazepin-2-one8C-278 3-(N′-(3- 3-(Trifluoromethyl)butyric3-(L-alaninyl)amino-7-chloro-5- C-E 543.1 (Trifluoromethyl)butyryl)-L-acid (2-chlorophenyl)-2,3-dihydro-1- 545.1 alaninyl)amino-7-chloro-5-(2-(Fluorochem) methyl-1H-1,4-benzodiazepin-2- chlorophenyl)-2,3-dihydro-1-one methyl-1H-1,4-benzodiazepin-2- (Example 8-F) one 8C-279 3-(N′-(3-3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-5-(2- C-E 481.1(Trifluoromethyl)butyryl)-L- acid thienyl)-2,3-dihydro-1-methyl-alaninyl)amino-5-(2-thienyl)-2,3- (Fluorochem)1H-1,4-benzodiazepin-2-one dihydro-1-methyl-1H-1,4- (Example C-AL)benzodiazepin-2-one 8C-280 3-(N′-(3- 3-(Trifluoromethyl)butyric3-(L-alaninyl)amino-5- C-B 481.2 (Trifluoromethyl)butyryl)-L- acidcyclohexyl-2,3-dihydro-1- alaninyl)amino-5-cyclohexyl-2,3- (Fluorochem)methyl-1H-1,4-benzodiazepin-2- dihydro-1-methyl-1H-1,4- onebenzodiazepin-2-one (Example 8-G) 8C-281 3-(N′-(3-3-(Trifluoromethyl)butyric 3-(L-alaninyl)amino-7-bromo-5- C-B 573.1(Trifluoromethyl)butyryl)-L- acid (2-fluorophenyl)-2,3-dihydro-1- 574.1alaninyl)amino-7-bromo-5-(2- (Fluorochem) methyl-1H-1,4-benzodiazepin-2-fluorophenyl)-2,3-dihydro-1- one methyl-1H-1,4-benzodiazepin-2- (Example8-D) one 8C-282 3-(N′-(3- 3-(Trifluoromethyl)butyric3-(L-alaninyl)-amino-)2,4- C-E 541.3 (Trifluoromethyl)butyryl)-L- aciddioxo-1,5-bis-(2,2- alaninyl)-amino-)2,4-dioxo-1,5- (Fluorochem)dimethylpropyl)-2,3,4,5- bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine(Example 8-V) 8C-283 3-(N′-(4,4,4-Trifluorobutyryl)-L-4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-2,3- C-E 557.2alaninyl)amino-2,3-dihydro-5- (Fluorochem) dihydro-5-phenyl-1-(4,4,4-phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC) 8C-2843-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-1-(2-oxo-2- C-E 565.2 alaninyl)amino-1-(2-oxo-2-(Fluorochem) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2- one one(Example C-AB) 8C-285 3-(N′-(4,4,4-Trifluorobutyryl)-L-4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-1-methyl- C-E 468.1alaninyl)amino-1-methyl-2,3- (Fluorochem)2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-2863-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-7-chloro- C-E 495.1 alaninyl)amino-7-chloro-2,3-(Fluorochem) 2,3-dihydro-1-methyl-5-phenyl-dihydro-1-methyl-5-phenyl-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example 8-C) 8C-2873-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-7-chloro-5- C-E 529.1 alaninyl)amino-7-chloro-5-(2-(Fluorochem) (2-chlorophenyl)-2,3-dihydro-1- 531.1chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-2883-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-(2- C-E 467.1 alaninyl)amino-5-(2-thienyl)-2,3-(Fluorochem) thienyl)-2,3-dihydro-1-methyl dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI) 8C-2893-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5- C-E 467.2 alaninyl)amino-5-cyclohexyl-2,3-(Fluorochem) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-290 3-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-7-bromo-5- C-E 559.1 alaninyl)amino-7-bromo-5-(2-(Fluorochem) (2-fluorophenyl)-2,3-dihydro-1- 560.1fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-291 3-(N′-(4,4,4-Trifluorobutyryl)- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)-amino-)-2,4- C-E 527.3 L-alaninyl)-amino-)-2,4-dioxo-(Fluorochem) dioxo-1,5-bis-(2,2- 1,5-bis-(2,2-dimethylpropyl)-dimethylpropyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepine benzodiazepine (Example 8-V) 8C-292 3-(N′-(Isovaleryl)-L-Isovaleric acid 3-(L-alaninyl)amino-2,3- C-E 517.2alaninyl)amino-2,3-dihydro-5- (Aldrich) dihydro-5-phenyl-1-(4,4,4-phenyl-1-(4,4,4-trifluorobutyl)- trifluorobutyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AC) 8C-2933-(N′-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-1-(2-oxo-2-C-E 525.3 alaninyl)amino-1-(2-oxo-2- (Aldrich)phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2- one one(Example C-AB) 8C-294 3-(N′-(Isovaleryl)-L- Isovaleric acid3-(L-alaninyl)amino-1-methyl- C-E 428.2 alaninyl)amino-1-methyl-2,3-(Aldrich) 2,3-dihydro-5-(2-thiazolyl)-1H dihydro-5-(2-thiazolyl)-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-2953-(N′-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-7-chloro- C-E455.2 alaninyl)amino-7-chloro-2,3- (Aldrich)2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C) 8C-2963-(N′-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-7-chloro-5-C-E 489.1 alaninyl)amino-7-chloro-5-(2- (Aldrich)(2-chlorophenyl)-2,3-dihydro-1- 491.1 chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2- methyl-1H-1,4-benzodiazepin-2- one one(Example 8-F) 8C-297 3-(N′-(Isovaleryl)-L- Isovaleric acid3-(L-alaninyl)amino-5-(2- C-B 427.1 alaninyl)amino-5-(2-thienyl)-2,3-(Aldrich) thienyl)-2,3-dihydro-1-methyl dihydro-1-methyl-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AI) 8C-2983-(N′-(Isovaleryl)-L- Isovaleric acid 3-(L-alaninyl)amino-5- C-B 427.2alaninyl)amino-5-cyclohexyl-2,3- (Aldrich) cyclohexyl-2,3-dihydro-1-dihydro-1-methyl-1H-1,4- methyl-1H-1,4-benzodiazepin-2-benzodiazepin-2-one one (Example 8-G) 8C-299 3-(N′-(Isovaleryl)-L-Isovaleric acid 3-(L-alaninyl)amino-7-bromo-5- C-B 519.1alaninyl)amino-7-bromo-5-(2- (Aldrich) (2-fluorophenyl)-2,3-dihydro-1-520.1 fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-300 3-(N′-(Isovaleryl)-L-alaninyl)- Isovaleric acid 3-(L-alaninyl)-amino-)-2,4-C-E 487.3 amino-)-2,4-dioxo-1,5-bis-(2,2- (Aldrich) dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5- dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5-tetrahydro-1H-1,5- benzodiazepine benzodiazepine (Example 8-V) 8C-3013-(N′-(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-2,3- C-E547.3 Hydroxyisocaproyl)-L- acid dihydro-5-phenyl-1-(4,4,4-alaninyl)amino-2,3-dihydro-5- (Aldrich) trifluorobutyl)-1H-1,4-phenyl-1-(4,4,4-trifluorobutyl)- benzodiazepin-2-oneill-1,4-benzodiazepin-2-one (Example C-AC) 8C-302 3-(N′-(L-alpha-L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-1-(2-oxo-2- C-E 555.3Hydroxyisocaproyl)-L- acid phenylethyl)-2,3-dihydro-5-alaninyl)amino-1-(2-oxo-2- (Aldrich) phenyl-1H-1,4-benzodiazepin-2-phenylethyl)-2,3-dihydro-5- one phenyl-1H-1,4-benzodiazepin-2- (ExampleC-AB) one 8C-303 3-(N′-(L-alpha- L-alpha-Hydroxyisocaproic3-(L-alaninyl)amino-1-methyl- C-E 458.2 Hydroxyisocaproyl)-L- acid2,3-dihydro-5-(2-thiazolyl)-1H- alaninyl)amino-1-methyl-2,3- (Aldrich)1,4-benzodiazepin-2-one dihydro-5-(2-thiazolyl)-1H-1,4- (Example C-AH)benzodiazepin-2-one 8C-304 3-(N′-(L-alpha- L-alpha-Hydroxyisocaproic3-(L-alaninyl)amino-7-chloro- C-E 485.2 Hydroxyisocaproyl)-L- acid2,3-dihydro-1-methyl-5-phenyl- alaninyl)amino-7-chloro-2,3- (Aldrich)1H-1,4-benzodiazepin-2-one dihydro-1-methyl-5-phenyl-1H- (Example 8-C)1,4-benzodiazepin-2-one 8C-305 3-(N′-(L-alpha- L-alpha-Hydroxyisocaproic3-(L-alaninyl)amino-7-chloro-5- C-E 519.1 Hydroxyisocaproyl)-L- acid(2-chlorophenyl)-2,3-dihydro-1- 521.1 alaninyl)amino-7-chloro-5-(2-(Aldrich) methyl-1H-1,4-benzodiazepin-2- chlorophenyl)-2,3-dihydro-1-one methyl-1H-1,4-benzodiazepin-2- (Example 8-F) one 8C-3063-(N′-(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-5-(2- C-E457.1 Hydroxyisocaproyl)-L- acid thienyl)-2,3-dihydro-1-methyl-alaninyl)amino-5-(2-thienyl)-2,3- (Aldrich) 1H-1,4-benzodiazepin-2-onedihydro-1-methyl-1H-1,4- (Example C-AI) benzodiazepin-2-one 8C-3073-(N′-(L-alpha- L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-5- C-E457.3 Hydroxyisocaproyl)-L- acid cyclohexyl-2,3-dihydro-1-alaninyl)amino-5-cyclohexyl-2,3- (Aldrich)methyl-1H-1,4-benzodiazepin-2- dihydro-1-methyl-1H-1,4- onebenzodiazepin-2-one (Example 8-G) 8C-308 3-(N′-(L-alpha-L-alpha-Hydroxyisocaproic 3-(L-alaninyl)amino-7-bromo-5- C-B 549.1Hydroxyisocaproyl)-L- acid (2-fluorophenyl)-2,3-dihydro-1- 550.2alaninyl)amino-7-bromo-5-(2- (Aldrich) methyl-1H-1,4-benzodiazepin-2-fluorophenyl)-2,3-dihydro-1- one methyl-1H-1,4-benzodiazepin-2- (Example8-D) one 8C-309 3-( N′-(L-alpha- L-alpha-Hydroxyisocaproic3-(L-alaninyl)-amino-)-2,4- C-B 517.3 Hydroxyisocaproyl)-L-alaninyl)-acid dioxo-1,5-bis-(2,2- amino-)-2,4-dioxo-1,5-bis-(2,2- (Aldrich)dimethylpropyl)-2,3,4,5- dimethylpropyl)-2,3,4,5- tetrahydro-1H-1,5-tetrahydro-1H-1,5- benzodiazepine benzodiazepine (Example 8-V) 8C-3103-(N′-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid 3-(L-alaninyl)amino-2,3-C-B 567.2 alaninyl)amino-2,3-dihydro-5- (Sigma)dihydro-5-phenyl-1-(4,4,4- phenyl-1-(4,4,4-trifluorobutyl)-trifluorobutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-AC) 8C-311 3-(N′-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid3-(L-alaninyl)amino-1-(2-oxo-2- C-B 575.2 alaninyl)amino-1-(2-oxo-2-(Sigma) phenylethyl)-2,3-dihydro-5- phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2- phenyl-1H-1,4-benzodiazepin-2- one one(Example C-AB) 8C-312 3-(N′-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid3-(L-alaninyl)amino-1-methyl- C-E 478.1 alaninyl)amino-1-methyl-2,3-(Sigma) 2,3-dihydro-5-(2-thiazolyl)-1H- dihydro-5-(2-thiazolyl)-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AH) 8C-3133-(N′-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid3-(L-alaninyl)amino-7-chloro- C-E 505.2 alaninyl)amino-7-chloro-2,3-(Sigma) 2,3-dihydro-1-methyl-5-phenyl- dihydro-1-methyl-5-phenyl-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example 8-C) 8C-3143-(N′-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid3-(L-alaninyl)amino-7-chloro-5- C-E 539.1 alaninyl)amino-7-chloro-5-(2-(Sigma) (2-chlorophenyl)-2,3-dihydro-1- 541.1chlorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-F) 8C-3153-(N′-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid3-(N′-(L-alaninyl)amino-5-(2- C-E 477.1alaninyl)amino-5-(2-thienyl)-2,3- (Sigma) thienyl)-2,3-dihydro-1-methyl-dihydro-1-methyl-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-AI) 8C-316 3-(N′-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid3-(L-alaninyl)amino-5- C-E 477.2 alaninyl)amino-5-cyclohexyl-2,3-(Sigma) cyclohexyl-2,3-dihydro-1- dihydro-1-methyl-1H-1,4-methyl-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example 8-G)8C-317 3-(N′-(L-(+)-Mandelyl)-L- L-(+)-Mandelic acid3-(L-alaninyl)amino-7-bromo-5- C-E 567.1 alaninyl)amino-7-bromo-5-(2-(Sigma) (2-fluorophenyl)-2,3-dihydro-1- 569.1fluorophenyl)-2,3-dihydro-1- methyl-1H-1,4-benzodiazepin-2-methyl-1H-1,4-benzodiazepin-2- one one (Example 8-D) 8C-3183-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 585.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(3-fluorobenzyl)- dihydro-1-(3-fluorobenzyl)-1H-(Aldrich) 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (ExampleC-A) 8C-319 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 567.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(benzyl)-1H-1,4- dihydro-1-(benzyl)-1H-1,4- (Aldrich)benzodiazepin-2-one benzodiazepin-2-one (Example C-B) 8C-3203-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- 11 623.2 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(4-tert- dihydro-1-(4-tert-butylbenzyl)- (Aldrich)butylbenzyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-C) 8C-321 3-(N′-(3,5-Difluorophenylacetyl)-3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 587.2L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-(2-dihydro-1-(2-cyclohexylethyl)- (Aldrich) cyclohexylethyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-D) 8C-3223-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 561.2 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(3,3- dihydro-1-(3,3-dimethylbutyl)- (Aldrich)dimethylbutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-E) 8C-323 3-(N′-(3,5-Difluorophenylacetyl)-3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 625.1L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-(1-dihydro-1-(1-methoxycarbonyl-1- (Aldrich) methoxycarbonyl-1-phenylmethyl)-1H-1,4- phenylmethyl)-1H-1,4- benzodiazepin-2-onebenzodiazepin-2-one (Example C-F) 8C-3243-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 561.2 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(2-ethylbutyl)- dihydro-1-(2-ethylbutyl)-1H-1,4-(Aldrich) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-G)8C-325 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 573.2 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1- dihydro-1-(cyclohexylmethyl)- (Aldrich)(cyclohexylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-H) 8C-3263-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 581.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(2-phenylethyl)- dihydro-1-(2-phenylethyl)-1H-(Aldrich) 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (ExampleC-I) 8C-327 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 595.2 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(3-phenylpropyl)- dihydro-1-(3-phenylpropyl)-1H-(Aldrich) 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (ExampleC-J) 8C-328 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 650.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(2-(N- dihydro-1-(2-(N- (Aldrich)phthalimidyl)ethyl)-1H-1,4- phthalimidyl)ethyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-K) 8C-3293-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 643.2 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(2- dihydro-1-(2-biphenylmethyl)- (Aldrich)biphenylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-L) 8C-330 3-(N′-(3,5-Difluorophenylacetyl)-3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 561.1L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-((2- dihydro-1-((2-(Aldrich) tetrahydrofuranyl)methyl)-1H- tetrahydrofuranyl)methyl)-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-M) 8C-3313-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 625.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(2-( 1,4- dihydro-1-(2-(1,4- (Aldrich)benzodioxanyl)methyl)-1H-1,4- benzodioxanyl)methyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-N) 8C-3323-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 657.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-((3-(5- dihydro-1-(3-(5-chlorobenzo[b] (Aldrich)chlorobenzo[b]thienyl))methyl)- thienyl)methyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-O) 8C-3333-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 575.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(3,3-dimethyl-2- dihydro-1-(3,3-dimethyl-2-oxo-(Aldrich) oxo-propyl)-1H-1,4- propyl)-1H-1,4-benzodiazepin-2-benzodiazepin-2-one one (Example C-P) 8C-3343-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 609.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(5- dihydro-1-(5- (Aldrich)benzofurazanylmethyl)-1H-1,4- benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-Q) 8C-3353-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 611.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(3- dihydro-1-(3-phenoxypropyl)-1H- (Aldrich)phenoxypropyl)-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one8C-336 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 686.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(6-(2- dihydro-1-(6-(2- (Aldrich)trifluoromethylquinolinyl)methyl)- trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one 1H-1,4-benzodiazepin-2-one (Example C-S)8C-337 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 547.2 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(2-methylbutyl)- dihydro-1-(2-methylbutyl)-1H-(Aldrich) 1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (ExampleC-T) 8C-338 3-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-G 505.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(ethyl)-1H-1,4- dihydro-1-(ethyl)-1H-1,4- (Aldrich)benzodiazepin-2-one benzodiazepin-2-one (Example C-U) 8C-3393-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- C-I 568.1 L-alaninyl)amino-5-phenyl-2,3-acid 2,3-dihydro-1-(3- dihydro-1-(3-pyridylmethyl)-1H- (Aldrich)pyridylmethyl)-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-V) 8C-340 3-(N′-(3,5-Difluorophenylacetyl)-3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 676.2L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-(2-oxo-2-(N-dihydro-1-(2-oxo-2-(N- (Aldrich) indolinyl)ethyl)-1H-1,4-indolinyl)ethyl)-1H-1,4- benzodiazepin-2-one benzodiazepin-2-one(Example C-W) 8C-341 3-(N′-(3,5-Difluorophenylacetyl)-3,5-Difluorophenylacetic 3-(L-alaninyl)amino-5-phenyl- C-G 586.1L-alaninyl)amino-5-phenyl-2,3- acid 2,3-dihydro-1-((4-(3,5-dihydro-1-(4-(3,5- (Aldrich) dimethyl)isoxazolyl)methyl)-1H-dimethylisoxazolyl)methyl)-1H- 1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-Y) 8C-3423-(N′-(3,5-Difluorophenylacetyl)- 3,5-Difluorophenylacetic3-(L-alaninyl)amino-5-phenyl- L-alaninyl)amino-5-phenyl-2,3- acid2,3-dihydro-1-(2-methoxyethyl)- dihydro-1-(2-methoxyethyl)-1H- (Aldrich)1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-Z) 8C-3433-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 523.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(benzyl)-1H-1,4- dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-B) 8C-3443-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 579.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(4-tert- dihydro-1-(4-tert-butylbenzyl)-butylbenzyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-C) 8C-345 3-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 543.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(2- dihydro-1-(2-cyclohexylethyl)-cyclohexylethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-D) 8C-346 3-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 517.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(3,3- dihydro-1-(3,3-dimethylbutyl)-dimethylbutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-E) 8C-347 3-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 475.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(isopropyl)-1H- dihydro-1-(isopropyl)-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-L) 8C-3483-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 581.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(1- dihydro-1-(1-methoxycarbonyl-1-methoxycarbonyl-1- phenylmethyl)-1H-1,4- phenylmethyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-F) 8C-3493-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 517.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(2-ethylbutyl)- dihydro-1-(2-ethylbutyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-G) 8C-3503-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 529.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1- dihydro-1-(cyclohexylmethyl)-(cyclohexylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-H) 8C-351 3-(N′-(Cyclopentylacetyl)-L-Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 537.2alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-1-(2-phenylethyl)-dihydro-1-(2-phenylethyl)-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-I) 8C-3523-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 551.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(3-phenylpropyl)- dihydro-1-(3-phenylpropyl)-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-J) 8C-3533-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 606.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(2-(N- dihydro-1-(2-(N-phthalimidyl)ethyl)-1H-1,4- phthalimidyl)ethyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-K) 8C-3543-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 599.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(2- dihydro-1-(2-biphenylmethyl)-biphenylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-L) 8C-355 3-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 613.1 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(3-(5- dihydro-1-(3-(5-chlorobenzo[b]chlorobenzo[b]thienyl)methyl)- thienyl)methyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-O) 8C-3563-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 531.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(3,3-dimethyl-2- dihydro-1-(3,3-dimethyl-2-oxo-oxo-butyl)-1H-1,4- butyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-oneone (Example C-P) 8C-357 3-(N′-(Cyclopentylacetyl)-L- Cyclopentylaceticacid 3-(L-alaninyl)amino-5-phenyl- C-G 565.2alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-1-(5- dihydro-1-(5-benzofurazanylmethyl)-1H-1,4- benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-Q) 8C-3583-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 567.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(3- dihydro-1-(3-phenoxypropyl)-1H-phenoxypropyl)-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-R) 8C-359 3-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 642.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(6-(2- dihydro-1-(6-(2-trifluoromethylquinolinyl)methyl)- trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one 1H-1,4-benzodiazepin-2-one (Example C-S)8C-360 3-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 487.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1- dihydro-1-(cyclopropylmethyl)-(cyclopropylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example 8-L) 8C-361 3-(N′-(Cyclopentylacetyl)-L-Cyclopentylacetic acid 3-(L-alaninyl)amino-5-phenyl- C-G 503.2alaninyl)amino-5-phenyl-2,3- (Aldrich) 2,3-dihydro-1-(2-methylbutyl)-dihydro-1-(2-methylbutyl)-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-T) 8C-3623-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 461.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(ethyl)-1H-1,4- dihydro-1-(ethyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-U) 8C-3633-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 542.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(4-(3,5- dihydro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H- dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-Y) 8C-3643-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 475.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(propyl)-1H-1,4- dihydro-1-(propyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-L) 8C-3653-(N′-(Cyclopentylacetyl)-L- Cyclopentylacetic acid3-(L-alaninyl)amino-5-phenyl- C-G 491.2 alaninyl)amino-5-phenyl-2,3-(Aldrich) 2,3-dihydro-1-(methoxyethyl)- dihydro-1-(2-methoxyethyl)-1H-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-Z) 8C-3663-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 537.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(benzyl)-1H-1,4- dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-B) 8C-3673-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 593.2 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(4-tert- dihydro-1-(4-tert-butylbenzyl)-butylbenzyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-C) 8C-368 3-(N′-(4,4,4-Trifluorobutyryl)-L-4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 557.2alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-(2-dihydro-1-(2-cyclohexylethyl)- cyclohexylethyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-D) 8C-3693-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 531.2 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(3,3- dihydro-1-(3,3-dimethylbutyl)-dimethylbutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-E) 8C-370 3-(N′-(4,4,4-Trifluorobutyryl)-L-4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 489.1alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-(isopropyl)-1H-dihydro-1-(isopropyl)-1H-1,4- 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example 8-L) 8C-3713-N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 595.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(1- dihydro-1-(1-methoxycarbonyl-1-methoxycarbonyl-1- phenylmethyl)-1H-1,4- phenylmethyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-F) 8C-3723-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 531.2 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(2-ethylbutyl)-dihydro-1-(2-ethylbutyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-G) 8C-3733-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 543.2 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1- dihydro-1-(cyclohexylmethyl)-(cyclohexylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-H) 8C-3743-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 565.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(3-phenylpropyl)dihydro-1-(3-phenylpropyl)-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-J) 8C-3753-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 613.2 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(2- dihydro-1-(2-biphenylmethyl)-biphenylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-L) 8C-376 3-(N′-(4,4,4-Trifluorobutyryl)-L-4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 627.1alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-(3-(5-dihydro-1-(3-(5-chlorobenzo[b] chlorobenzo[b]thienyl)methyl)-thienyl)methyl)-1H-1,4- 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-O) 8C-377 3-(N′-(4,4,4-Trifluorobutyryl)-L-4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 545.2alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-(3,3-dimethyl-2-dihydro-1-(3,3-dimethyl-2-oxo- oxo-butyl)-1H-1,4-butyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example C-P)8C-378 3-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 579.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(5- dihydro-1-(5-benzofurazanylmethyl)-1H-1,4- benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-Q) 8C-3793-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 581.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(3- dihydro-1-(3-phenoxypropyl)-1H-phenoxypropyl)-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example C-R) 8C-380 3-(N′-(4,4,4-Trifluorobutyryl)-L-4,4,4-Trifluorobutyric acid 3-(L-alaninyl)amino-5-phenyl- C-G 656.1alaninyl)amino-5-phenyl-2,3- (Fluorochem) 2,3-dihydro-1-(6-(2-dihydro-1-(6-(2- trifluoromethylquinolinyl)methyl)-trifluoromethylquinolinyl)methyl)- 1H-1,4-benzodiazepin-2-one1H-1,4-benzodiazepin-2-one (Example C-S) 8C-3813-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 501.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1- dihydro-1-(cyclopropylmethyl)-(cyclopropylmethyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example 8-L) 8C-3823-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 517.2 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(2-methylbutyl)-dihydro-1-(2-methylbutyl)-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-T) 8C-3833-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 475.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(ethyl)-1H-1,4- dihydro-1-(ethyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-U) 8C-3843-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 556.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(4-(3,5- dihydro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H- dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one (Example C-Y) 8C-3853-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 489.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(propyl)-1H-1,4- dihydro-1-(propyl)-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-L) 8C-3863-(N′-(4,4,4-Trifluorobutyryl)-L- 4,4,4-Trifluorobutyric acid3-(L-alaninyl)amino-5-phenyl- C-G 505.1 alaninyl)amino-5-phenyl-2,3-(Fluorochem) 2,3-dihydro-1-(2-methoxyethyl)-dihydro-1-(2-methoxyethyl)-1H- 1H-1,4-benzodiazepin-2-one1,4-benzodiazepin-2-one (Example C-Z) 8C-387 3-(N′-(L-(+)-Mandelyl)-L-L-(+)-Mandelic acid 3-(L-alaninyl)-amino-)-2,4- C-E 537.3alaninyl)-amino-)-2,4-dioxo-1,5- (Sigma) dioxo-1,5-bis-(2,2-bis-(2,2-dimethylpropyl)-2,3,4,5- dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepine benzodiazepine(Example 8-L) 8C-388 (S)-3-(N′-(N-pyrrolidinylacetyl)- Pyrrolidine(S)-3-( N′-(chloroacetyl)-L- C-F L-alaninyl)amino-2,3-dihydro-1-(Aldrich) alaninyl)amino-2,3-dihydro-1- methyl-5-phenyl-1H-1,4-methyl-5-phenyl-1H-1,4- benzodiazepin-2-one benzodiazepin-2-one (ExampleC-AD) 8C-389 3-(N′-(o-Chlorophenoxyacetyl)- o-Chlorophenoxyacetic acid3-(L-alaninyl)amino-2,3- C-A 504.8 L-alaninyl)amino-2,3-dihydro-1-(Lancaster) dihydro-1-methyl-5-phenyl-1H methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-3903-(N′-(2-Thiopheneacetyl)-L- 2-Thiopheneacetic acid3-(L-alaninyl)amino-2,3- C-A 460.8 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-3913-(N′-(3- 3- 3-(L-alaninyl)amino-2,3- C-A 523.1(Trifluoromethyl)phenylacetic)- (Trifluoromethyl)phenyl-dihydro-1-methyl-5-phenyl-1H L-alaninyl)amino-2,3-dihydro-1- acetic acid1,4-benzodiazepin-2-one methyl-5-phenyl -1H-1,4- (Marshallton) (Example8-B) benzodiazepin-2-one 8C-392 3-(N′-(p-Tolylacetyl)-L- p-Tolylaceticacid 3-(L-alaninyl)amino-2,3- C-A 468.8 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl -1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-3933-(N′-(3-(4- 3-(4- 3-(L-alaninyl)amino-2,3- C-A 498.8Methoxyphenyl)propionyl)-L- Methoxyphenyl)propionicdihydro-1-methyl-5-phenyl-1H- alaninyl)amino-2,3-dihydro-1- acid1,4-benzodiazepin-2-one methyl-5-phenyl-1H-1,4- (Aldrich) (Example 8-B)benzodiazepin-2-one 8C-394 3-(N′-(3,5-Difluorophenylacetyl)-3,5-Difluorophenylacetic 3-(L-alaninyl)amino-2,3- C-A 491.0L-alaninyl)amino-2,3-dihydro-1- acid dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- (Aldrich) 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example 8-B) 8C-395 3-(N′-(m-Tolylacetyl)-L-m-Tolylacetic acid 3-(L-alaninyl)amino-2,3- C-A 468.6alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-396 3-(N′-(3-Fluorophenylacetyl)-L-3-Fluorophenylacetic acid 3-(L-alaninyl)amino-2,3- C-A 472.8alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-397 3-(N′-(3-Bromophenylacetyl)-L- 3-Bromophenylaceticacid 3-(L-alaninyl)amino-2,3- C-A 535.0 alaninyl)amino-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B) 8C-3983-(N′-(4-Chlorophenoxyacetyl)- 4-Chlorophenoxyacetic acid3-(L-alaninyl)amino-2,3- C-A 505.0 L-alaninyl)amino-2,3-dihydro-1-(Grand Island Biological dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- Company) 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example 8-B) 8C-399 3-(N′-(2-Naphthylacetyl)-L-2-Naphthylacetic acid 3-(L-alaninyl)amino-2,3- C-A 505.0alaninyl)amino-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-phenyl-1H-methyl-5-phenyl-1H-1,4- 1,4-benzodiazepin-2-one benzodiazepin-2-one(Example 8-B) 8C-400 3-(N′-(3-Methylphenoxyacetyl)-3-Methylphenoxyacetic acid 3-(L-alaninyl)amino-2,3- C-A 489.0L-alaninyl)amino-2,3-dihydro-1- (Lancaster)dihydro-1-methyl-5-phenyl-1H- methyl-5-phenyl-1H-1,4-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example 8-B)

General Procedure C-J

[2879] A vial was charged with a CHCl₃ solution of Starting material 1(71 umol), a DMF solution of HOBt monohydrate (71 umol), a CHCl₃solution of diisopropylcarbodiimide (71 umol), and a CHCl₃ solution ofstarting material 2 (60 umol). The vial was capped and the solutionallowed to stand at room temperature for two days. The reaction mixturewas loaded onto a cation exchange column, washed with MeOH and elutedwith 2 N NH₃/MeOH. The eluents were concentrated and dried to give thedesired product as determined by MS (IS) and HPLC.

General Procedure C-K

[2880] To a 4 mL vial was added 870 uL of 0.05 mM stock solution ofstarting material 1 in DMF/chloroform, 1000 uL of a 0.05 mM stocksolution of starting material 2 in chloroform, 1000 uL of a 0.05 mMstock solution of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide inchloroform and 100 uL of a 0.48 mM stock solution of HOBt in DMF. Afterstanding undisturbed for 48 h, the reaction mixture was concentrated andthe residue redissolved in 2 mL of a 10% methanol/methylene chloridesolution. This solution was then filtered through a pre-washed(methanol) 500 mg SCX column using an additional 8 mL of the samesolvent. The filtrate was concentrated under a stream of nitrogen toapproximately ⅓ its original volume and then passed over a plug (200 mg)of AG 1-8x anion exchange resin (BioRad; Hercules, California; Columnswere pre-washed with 1N NaOH, water and methanol) using an additional 6mL of 10% methanol/methylene chloride solution. The resulting filtratewas concentrated under vacuum and the crude products were submitted fortesting without further purification. Product structure and purity wereconfirmed by HPLC and IEX MS.

Example C-AE Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-oneStep A: Synthesis of3-Amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[2881] The title compound was synthesized as described in Synth.Commun., 26(4), 721-727 (1996).

Step B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[2882] A solution of L-Boc-alanine (1.74 g, 9.20 mmol), HOBt monohydrate(1.24 g, 9.20 mmol), diisopropylethylamime (1.6 mL, 9.20 mmol) andCH₂Cl₂ (30 mL) was purged with nitrogen and cooled in an ice bath. Tothe cold solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodimidehydrochloride (1.76 g, 9.20 mmol) followed by a solution of3-amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(2.45 g, 9.20 mmol) dissolved in CH₂Cl₂ (15 mL). The cold bath wasremoved and the solution stirred overnight at room temperature. Thereaction mixture was extracted with H₂O, 0, 0.1 N aq. citric acid, 5%aq. NaHCO₃, and brine. The remaining CH₂Cl₂ solution was dried (MgSO₄)and concentrated to a tan foam. The title compound was crystallized fromCH₂Cl₂/EtOAc to give 3.47 g (86% yield) of white crystals, mp. 228-229°C.

[2883] Anal. Calcd for C₂₃H₂₇N₅O₄: C, 63.14; H, 6.22; N, 16.01. Found:C, 63.25; H, 6.15; N, 15.95. MS (FD⁺) 437 m/z.

Step C: Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[2884] A solution of3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(3.42 g, 7.82 mmol) in CH₂Cl₂ (90 mL) was cooled in an ice bath andtreated with TFA (13.2 mL, 172 mmol). The cold bath was removed and thesolution stirred at room temperature for four hours. The reactionmixture was washed with 1 M aq. K₂CO₃ and the aqueous back-extractedwith CH₂Cl₂. The combined extracts were washed with H₂O, dried (MgSO₄)and concentrated to obtain 1.75 g (66% yield) of the title compound asan off-white foam. MS (IS⁺) 338 (m/e).

[2885]₁HNMR (CDCl₃): δ=8.76-8.86 (1H, m), 8.63 (1H, m), 8.17 (1H, m),7.82 (2H, m), 7.60 (1H, m), 7.41 (3H, m), 5.60 (1H, m), 3.63 (1H, m),3.49 (3H, s), 1.66 (2H, broad), 1.45 (3H, m).

Example C-AF Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one Step A: Synthesis of3-Amino-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[2886] The title compound was synthesized as described in Synth.Commun., 26(4), 721-727 (1996).

Step B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[2887] A solution of L-Boc-alanine (1.80 g, 9.50 mmol), HOBt monohydrate(1.28 g, 9.50 mmol), diisopropylethylamime (1.65 mL, 9.50 mmol) andCH₂Cl₂ (40 mL) was purged with nitrogen and cooled in an ice bath. Tothe cold solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodimidehydrochloride (1.82 g, 9.50 mmol) followed by a solution of3-amino-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(3.34 g, 9.50 mmol) dissolved in CH₂Cl₂ (25 mL). The cold bath wasremoved and the solution stirred overnight at room temperature. Thereaction mixture was extracted with H₂O, 5% aq. NaHCO₃, and brine. Theremaining CH₂Cl₂ solution was dried (MgSO₄) and concentrated to a tanfoam. The title compound was isolated via column chromatography (2%MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂) to give 3.53 g (71% yield) of yellowfoam.

[2888] MS (FD⁺) 522 (m/z).

[2889]¹HNMR (CDCl₃): δ=8.62 (1H, d), 8.11 (1H, m), 7.80 (2H, m), 7.59(2H, m), 7.32-7.45 (2H, m), 5.54 (1H, m), 5.02-5.18 (1H, m), 4.38 (1H,m), 4.20 (1H, m), 3.83 (1H, m), 2.62 (2H, t), 2.44 (4H, m), 1.40-1.56(12H, m), 0.88 (6H, m).

Step C: Synthesis of 3-[(L-Alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[2890] The title compound was synthesized using the procedure describedin Example C-AE, Step C. A solution of3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(3.52 g, 6.73 mmol) was treated with TFA (11.4 mL, 148 mmol) to give2.61 g (92% yield) the title compound as a light yellow foam.

[2891] MS (IS⁺) 423 (m/e).

[2892]¹HNMR (CDCl₃): δ=8.78-8.93 (1H, m), 8.62 (1H,d), 8.11 (1H, m),7.80 (2H, m), 7.58 (2H, m), 7.39 (2H, m), 5.58 (1H, m), 4.22 (1H, m),3.88 (1H, m), 3.61 (1H, m), 2.67 (2H, t), 2.49 (4H, m), 1.73 (2H,broad), 1.42 (3H, m), 0.91 (6H, m).

Example C-AG Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4benzodiazepin-2-oneStep A: Synthesis of3-Amino-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H1,4-benzodiazepin-2-one

[2893] The title compound was synthesized as described in Synth.Commun., 26(4), 721-727 (1996).

Step B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[2894] A solution of L-Boc-alanine (1.57 g, 8.33 mmol), HOBt monohydrate(1.13 g, 8.33 mmol), diisopropylethylamime (1.45 mL, 8.33 mmol) andCH₂Cl₂ (40 mL) was purged with nitrogen and cooled in an ice bath. Tothe cold solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodimidehydrochloride (1.60 g, 8.33 mmol) followed by a solution of3-amino-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one(2.92 g, 8.33 mmol) dissolved in CH₂Cl₂ (25 mL). The cold bath wasremoved and the solution stirred overnight at room temperature. Thereaction mixture was extracted with H₂O, 0.1 N aq. citric acid, 5% aq.NaHCO₃, and brine. The remaining CH₂Cl₂ solution was dried (MgSO₄) andconcentrated to a yellow foam. The title compound was isolated viacolumn chromatography (20% EtOAc/hexanes to 60% EtOAc/hexanes) to give4.19 g (96% yield) of light yellow foam.

[2895] MS (FD³⁰ ) 521 (m/z).

[2896]¹HNMR (CDCl₃): δ=8.65 (1H, t), 8.17 (1H, t), 7.90 (1H, t),7.71-7.85 (1H, m), 7.54 (1H, m), 7.44 (1H, t), 7.37 (1H, d), 7.24-7.32(1H, m), 7.14 (1H, m), 5.67 (1H, dd), 5.18 (1H, broad), 4.93-5.07 (1H,m), 4.504.64 (1H, m), 4.38 (1H, broad), 1.42-1.51 (12H, m), 1.26 (9H,d).

Step C: Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one

[2897] The title compound was synthesized using the procedure describedin Example C-AE, Step C. A solution of3-[(N-tert-butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxbutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (4.18 g, 8.01 mmol) was treated with TFA (13.6 mL, 176 mmol) togive 3.14 g (93% yield) the title compound as an off-white foam.

[2898] MS (IS³⁰ ) 422 (m/e).

[2899]¹HNMR (CDCl₃) δ8.85-8.99 (1H, m), 8.68 (1H, d), 8.20 (1H, t), 7.87(1H, t), 7.58 (1H, t), 7.42 ( 2H, m), 7.30 (1H, t), 7.17 (1H, d), 5.72(1H, m 5.08 (1H, d), 4.60 (1H, d), 3.66 (1H, m), 1.47 (3H, m), 1.28 (9H,m).

Example C-AH Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4benzodiazepin-2-oneStep A: Synthesis of3-Amino-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one

[2900] The title compound was synthesized in a manner similar to theprocedure described in Synth. Commun., 26(4), 721-727 (1996), startingwith 2-(2-aminobenzoyl)thiazole (prepared as described in Tetrahedron,51(3), 773-786, (1995)).

[2901] MS (IS³⁰ ) 273 (m/e).

[2902]¹HNMR (CDCl₃): δ=7.83-7.94 (2H, m), 7.61 (1H, t), 7.50 (1H, d),7.34 (2H, m), 4.60 (1H, s), 3.46 (3H, s), 1.97 (2H, broad).

Set B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one

[2903] A solution of L-Boc-alanine (1.85 g, 9.77 mmol), HOBt monohydrate(1.32 g, 9.77 mmol), diisopropylethylamime (1.70 mL, 9.77 mmol) andCH₂Cl₂ (30 mL) was purged with nitrogen and cooled in an ice bath. Tothe cold solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodimidehydrochloride (1.87 g, 9.77 mmol) followed by a solution of3-amino-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one(2.66 g, 9.77 mmol) dissolved in CH₂Cl₂ (20 mL). The cold bath wasremoved and the solution stirred overnight at room temperature. Thereaction mixture was extracted with H₂O, 0.1 N aq. citric acid, 5% aq.NaHCO₃, and brine. The remaining CH₂Cl₂ solution was dried (MgSO₄) andconcentrated to a light yellow foam. The title compound was crystallizedfrom EtOAc/hexane to give 3.22 g (74% yield) of white crystals, mp.196-197° C. Anal. Calcd for C₂₁H₂₅N₅O₄S: C, 56.87; H, 5.68; N, 15.79.Found: C, 56.74; H, 5.75; N, 15.55.

[2904] MS (IS³⁰ ) 444 m/e.

Step C: Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiazyl)-1H-1,4-benzodiazepin-2-one

[2905] The title compound was synthesized using the procedure describedin Example C-AE, Step C.

Example C-AI Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(thiophen-2-yl)-1H-1,4benzodiazepin-2-oneStep A: Synthesis of3-Amino-2,3-dihydro-1-methyl-5-(2-thiophen-2-yl)-1H-1,4-benzodiazepin-2-one

[2906] The title compound was synthesized in a manner similar to theprocedure described in

Synth. Commun., 26(4), 721-727 (1996), starting with2-(2-aminobenzoyl)thiophene (prepared as described in Collect. Czech.Chem. Commun., 34(2), 468-478, (1969)).

[2907] MS (IS⁺) 272 (m/e).

[2908]¹HNMR (CDCl₃): δ=7.68 (1H, d), 7.60 (1H, t), 7.48 (1H, m), 7.35(2H, d), 7.28 (1H, m), 7.15 (1H, d), 7.05 (1H, d), 4.50 (1H, broad),3.45 (3H, s), 2.26 (2H, broad).

Step B: Synthesis of3-[(N-tert-Butoxycarbonyl-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiophenyl)-1H-1,4-benzodiazepin-2-one

[2909] The title compound was synthesized in a manner similar to theprocedure described in Example C-AH, Step B.

[2910] MS (IS³⁰ ) 443 (m/e).

[2911]¹HNMR (CDCl₃): δ=7.69 (1H, d), 7.61 (2H, m), 7.48 (1H, d),7.27-7.42 (2H, m), 7.18 (1H, m), 7.05 (1H, m), 5.51 (1H, d), 5.13 (1H,broad), 4.36 (1H, broad), 3.44 (3H, s), 1.38-1.57 (12H, m).

Step C: Synthesis of3-[(L-Alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-thiophenyl)-1H-1,4-benzodiazepin-2-one

[2912] The title compound was synthesized in a manner similar to theprocedure described in Example C-AE, Step C.

[2913] MS (IS³⁰ ) 343 (m/e).

[2914]¹HNMR (CDCl₃): δ=8.55 (1H, d), 7.68 (1H, d), 7.59 (1H, m), 7.48(1H, d), 7.36 (1H, d), 7.31 ( 1H, d), 7.16 (1H, m), 7.04 (1H, t), 5.54(1H, d 3.58 (1H, m), 3.45 (3H, s), 1.41 (3H, d).

[2915] Using the procedures indicated, the compounds shown in Table C-2were prepared. TABLE C-2 Example General No. Compound Starting Material1 Starting Material 2 Procedure MS 8C-4013-[(N′-(4-methoxyphenylacetyl)-L- 4-Methoxyphenylacetic3-[(L-alaninyl)amino]-2,3- C-J 485.5 alaninyl)amino]-2,3-dihydro-1- aciddihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4- (Aldrich)1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4023-[(N′-(2-thiopheneacetyl)-L- 2-Thiopheneacetic acid3-[(L-alaninyl)amino]-2,3- C-J 461.5 alaninyl)amino]-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4033-[(N′-(3,5-difluorophenylacetyl)-L- 3,5-Difluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 491.5 alaninyl)amino]-2,3-dihydro-1- aciddihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4- (Aldrich)1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4043-[(N′-(3-bromophenylacetyl)-L- 3-Bromophenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 534.4 alaninyl)amino]-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4053-[(N′-(phenylmercaptoacetyl)-L- Phenylmercaptoacetic acid3-[(L-alaninyl)amino]-2,3- C-J 487.6 alaninyl)amino]-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4063-[(N′-(4-ethoxyphenylacetyl)-L- 4-Ethoxyphenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 499.6 alaninyl)amino]-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4073-[(N′-(4- 4- 3-[(L-alaninyl)amino]-2,3- C-J 523.5(trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenylaceticdihydro-1-methyl-5-(2-pyridyl)- alaninyl)amino]-2,3-dihydro-1- acid1H-1,4-benzodiazepin-2-one methyl-5-(2-pyridyl)-1H-1,4- (Aldrich)(Example C-AE) benzodiazepin-2-one 8C-408 3-[(N′-(3,5-3,5-bis(trifluoromethyl) 3-[(L-alaninyl)amino]-2,3- C-J 591.5bis(trifluoromethyl)phenylacetyl)-L- phenylacetic aciddihydro-1-methyl-5-(2-pyridyl)- alaninyl)amino]-2,3-dihydro-1- (Aldrich)1H-1,4-benzodiazepin-2-one methyl-5-(2-pyridyl)-1H-1,4- (Example C-AE)benzodiazepin-2-one 8C-409 3-[(N′-((methylthio)acetyl)-L-(methylthio)acetic acid 3-[(L-alaninyl)amino]-2,3- C-J 425.5alaninyl)amino]-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-(2-pyridyl)-methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AE) 8C-410 3-[(N′-(cyclohexylacetyl)-L-cyclohexylacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 461.6alaninyl)amino]-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-(2-pyridyl)-methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AE) 8C-4113-[(N′-(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic3-[(L-alaninyl)amino]-2,3- C-J 561.5 L-alaninyl)amino]-2,3-dihydro-1-acid dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-(Aldrich) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)8C-412 3-[(N′-(benzo[b]thiophene-3-acetyl)- benzo [b] thiophene-3-3-[(L-alaninyl)amino]-2,3- C-J 511.6 L-alaninyl)amino]-2,3-dihydro-1-acetic acid dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-(Lancaster) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (ExampleC-AE) 8C-413 3-[(N′-(2,4,6- 2,4,6-trimethylphenylacetic3-[(L-alaninyl)amino]-2,3- C-J 497.6 trimethylphenylacetyl)-L- aciddihydro-1-methyl-5-(2-pyridyl)- alaninyl)amino]-2,3-dihydro-1-(Lancaster) 1H-1,4-benzodiazepin-2-one methyl-5-(2-pyridyl)-1H-1,4-(Example C-AE) benzodiazepin-2-one 8C-414 3-[(N′-(4-biphenylacetyl)-L-4-biphenylacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 531.6alaninyl)amino]-2,3-dihydro-1- (Lancaster)dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4153-[(N′-(3,4-difluorophenylacetyl)-L- 3,4-difluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 491.5 alaninyl)amino]-2,3-dihydro-1- aciddihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4- (Aldrich)1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4163-[(N′-(4-(2-thienyl)butyryl)-L- 4-(2-thienyl)butyric acid3-[(L-alaninyl)amino]-2,3- C-J 489.6 alaninyl)amino]-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4173-[(N′-(5-methylhexanoyl)-L- 5-methylhexanoic acid3-[(L-alaninyl)amino]-2,3- C-J 449.5 alaninyl)amino]-2,3-dihydro-1-(P&B) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4183-[(N′-(3- mono-methyl succinate 3-[(L-alaninyl)amino]-2,3- C-J 451.5methoxycarbonylpropionyl)-L- (Aldrich) dihydro-1-methyl-5-(2-pyridyl)-alaninyl)amino]-2,3-dihydro-1- 1H-1,4-benzodiazepin-2-onemethyl-5-(2-pyridyl)-1H-1,4- (Example C-AE) benzodiazepin-2-one 8C-4193-[(N′-(methanesulfonylacetyl)-L- methanesulfonylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 457.5 alaninyl)amino]-2,3-dihydro-1-(Lancaster) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4203-[(N′-(4-toluenesulfonylacetyl)-L- 4-toluenesulfonylacetic3-[(L-alaninyl)amino]-2,3- C-J 533.6 alaninyl)amino]-2,3-dihydro-1- aciddihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4- (Lancaster)1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4213-[(N′-(2,6-difluoromandelyl)-L- 2,6-difluoromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 507.5 alaninyl)amino]-2,3-dihydro-1-(Fluorochem) dihydro-1-methyl-5-(2-pyridyl)-methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AE) 8C-422 3-[(N′-(4-fluoromandelyl)-L-4-fluoromandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 489.5alaninyl)amino]-2,3-dihydro-1- (Lancaster)dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4233-[(N′-(2,5-difluoromandelyl)-L- 2,5-difluoromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 507.5 alaninyl)amino]-2,3-dihydro-1-(Fluorochem) dihydro-1-methyl-5-(2-pyridyl)-methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AE) 8C-4243-[(N′-(2,4,6-trifluorophenylacetyl)- 2,4,6-trifluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 509.5 L-alaninyl)amino]-2,3-dihydro-1-acid dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-(Fluorochem) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (ExampleC-AE) 8C-425 3-[(N′-(4-fluoro-2- 4-fluoro-2- 3-[(L-alaninyl)amino]-2,3-C-J 541.5 (trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)dihydro-1-methyl-5-(2-pyridyl)- alaninyl)amino]-2,3-dihydro-1-phenylacetic acid 1H-1,4-benzodiazepin-2-onemethyl-5-(2-pyridyl)-1H-1,4- (Fluorochem) (Example C-AE)benzodiazepin-2-one 8C-426 3-[(N′-(4,4,4-trifluorobutyryl)-L-4,4,4-trifluorobutyric acid 3-[(L-alaninyl)amino]-2,3- C-J 461.4alaninyl)amino]-2,3-dihydro-1- (Fluorochem)dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4273-[(N′-(4-isopropylphenylacetyl)-L- 4-isopropylphenylacetic3-[(L-alaninyl)amino]-2,3- C-J 497.6 alaninyl)amino]-2,3-dihydro-1- aciddihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4- (Lancaster)1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4283-[(N′-(beta-phenyllactyl)-L- beta-phenyllactic acid3-[(L-alaninyl)amino]-2,3- C-J 485.5 alaninyl)amino]-2,3-dihydro-1-(Sigma) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4293-[(N′-(mandelyl)-L- mandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 471.5alaninyl)amino]-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-(2-pyridyl)-methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AE) 8C-430 3-[(N′-(4-chloromandelyl)-L-p-chloromandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 506.0alaninyl)amino]-2,3-dihydro-1- (Acros) dihydro-1-methyl-5-(2-pyridyl)-methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AE) 8C-431 3-[(N′-(isovaleryl)-L-isovaleric acid 3-[(L-alaninyl)amino]-2,3- C-J 421.5alaninyl)amino]-2,3-dihydro-1- (Aldrich) dihydro-1-methyl-5-(2-pyridyl)-methyl-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AE) 8C-4323-[(N′-(2,3,5-trifluorophenylacetyl)- 2,3,5-trifluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 509.5 L-alaninyl)amino]-2,3-dihydro-1-acid dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-(Fluorochem) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (ExampleC-AE) 8C-433 3-[(N′-(3-methylthiopropionyl)-L- 3-methylthiopropionicacid 3-[(L-alaninyl)amino]-2,3- C-J 439.5 alaninyl)amino]-2,3-dihydro-1-(Lancaster) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4343-[(N′-(L-alpha-hydroxyisocaproyl)- L-alpha-hydroxyisocaproic3-[(L-alaninyl)amino]-2,3- C-J 451.5 L-alaninyl)amino]-2,3-dihydro-1-acid dihydro-1-methyl-5-(2-pyridy)- methyl-5-(2-pyridyl)-1H-1,4-(Aldrich) 1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE)8C-435 3-[(N′-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 500.5 alaninyl)amino]-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4363-[(N′-(D-3-phenylacetyl)-L- D-3-phenyllactic acid3-[(L-alaninyl)amino]-2,3- C-J 485.5 alaninyl)amino]-2,3-dihydro-1-(Aldrich) dihydro-1-methyl-5-(2-pyridyl)- methyl-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AE) 8C-4373-[(N′-(4-methocyphenylacetyl)-L- 4-Methoxyphenylacetic3-[(L-alaninyl)amino]-2,3- C-J 569.6 alaninyl)amino]-2,3-dihydro-1-(3,3-acid dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-(Aldrich) oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-438 3-[(N′-(2-thiopheneacetyl)-L-2-Thiopheneacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 545.6alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4393-[(N′-(3,5-difluorophenylacetyl)-L- 3,5-Difluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 575.6 alaninyl)amino]-2,3-dihydro-1-(3,3-acid dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-(Aldrich) oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-4403-[(N′-(3-bromophenylacetyl)-L- 3-Bromophenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 618.5 alaninyl)amino]-2,3-dihydro-1-(3,3-(Aldrich) dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-4413-[(N′-(phenylmercaptoacetyl)-L- Phenylmercaptoacetic acid3-[(L-alaninyl)amino]-2,3- C-J 571.7 alaninyl)amino]-2,3-dihydro-1-(3,3-(Aldrich) dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-4423-[(N′-(4-ethoxyphenylacetyl)-L- 4-Ethoxyphenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 583.7 alaninyl)amino]-2,3-dihydro-1-(3,3-(Aldrich) dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-443 3-[(N′-(4- 4-3-[(L-alaninyl)amino]-2,3- C-J 607.6 (trifluoromethyl)phenylacetyl)-L-(trifluoromethyl)phenylacetic dihydro-1-(3,3-dimethyl-2-alaninyl)amino]-2,3-dihydro-1-(3,3- acid oxobutyl)-5-(2-pyridyl)-1H-1,4-dimethyl-2-oxobutyl)-5-(2-pyridyl)- (Aldrich) benzodiazepin-2-one1H-1,4-benzodiazepin-2-one (Example C-AG) 8C-444 3-[(N′-(3,5-3,5-Bis(trifluoromethyl) 3-[(L-alaninyl)amino]-2,3- C-J 675.6bis(trifluoromethyl)phenylacetyl)-L- phenylacetic aciddihydro-1-(3,3-dimethyl-2- alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich)oxobutyl)-5-(2-pyridyl)-1H-1,4- dimethyl-2-oxobutyl)-5-(2-pyridyl)-benzodiazepin-2-one 1H-1,4-benzodiazepin-2-one (Example C-AG) 8C-4453-[(N′-((methylthio)acetyl)-L- (methylthio)acetic acid3-[(L-alaninyl)amino]-2,3- C-J 509.6 alaninyl)amino]-2,3-dihydro-1-(3,3-(Aldrich) dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-446 3-[(N′-(cyclohexylacetyl)-L-cyclohexylacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 545.7alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4473-[(N′-(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic3-[(L-alaninyl)amino]-2,3- C-J 645.6 L-alaninyl)amino]-2,3-dihydro-1-acid dihydro-1-(3,3-dimethyl-2- (3,3-dimethyl-2-oxobutyl)-5-(2-(Aldrich) oxobutyl)-5-(2-pyridyl)-1H-1,4-pyridyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example C-AG)8C-448 3-[(N′-(benzo[b]thiophene-3-acetyl)- benzo [b] thiophene-3-3-[(L-alaninyl)amino]-2,3- C-J 595.7 L-alaninyl)amino]-2,3-dihydro-1-acetic acid dihydro-1-(3,3-dimethyl-2- (3,3-dimethyl-2-oxobutyl)-5-(2-(Lancaster) oxobutyl)-5-(2-pyridyl)-1H-1,4-pyridyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example C-AG)8C-449 3-[(N′-(2,4,6- 2,4,6-trimethylphenylacetic3-[(L-alaninyl)amino]-2,3- C-J 581.7 trimethylphenylacetyl)-L- aciddihydro-1-(3,3-dimethyl-2- alaninyl)amino]-2,3-dihydro-1-(3,3-(Lancaster) oxobutyl)-5-(2-pyridyl)-1H-1,4-dimethyl-2-oxobutyl)-5-(2-pyridyl)- benzodiazepin-2-one1H-1,4-benzodiazepin-2-one (Example C-AG) 8C-4503-[(N′-(4-biphenylacetyl)-L- 4-biphenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 615.7 alaninyl)amino]-2,3-dihydro-1-(3,3-(Lancaster) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4513-[(N′-(3,4-difluorophenylacetyl)-L- 3,4-difluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 575.6 alaninyl)amino]-2,3-dihydro-1-(3,3-acid dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-(Aldrich) oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-452 3-[(N′-(4-(2-thienyl)butyl)-L-4-(2-thienyl)butyric acid 3-[(L-alaninyl)amino]-2,3- C-J 573.7alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4533-[(N′-(5-methylhexanoyl)-L- 5-methylhexanoic acid3-[(L-alaninyl)amino]-2,3- C-J 533.7 alaninyl)amino]-2,3-dihydro-1-(3,3-(P&B) dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-454 3-[(N′-(3- mono-methylsuccinate 3-[(L-alaninyl)amino]-2,3- C-J 535.6methoxycarbonylpropionyl)-L- (Aldrich) dihydro-1-(3,3-dimethyl-2-alaninyl)amino]-2,3-dihydro-1-(3,3- oxobutyl)-5-(2-pyridyl)-1H-1,4-dimethyl-2-oxobutyl)-5-(2-pyridyl)- benzodiazepin-2-one1H-1,4-benzodiazepin-2-one 8C-455 3-[(N′-(methanesulfonylacetyl)-L-methanesulfonylacetic acid 3-[(L-alaninyl)amino]-2,3- C-J 541.6alaninyl)amino]-2,3-dihydro-1-(3,3- (Lancaster)dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-4563-[(N′-(4-toluenesulfonylacetyl)-L- 4-toluenesulfonylacetic3-[(L-alaninyl)amino]-2,3- C-J 617.7 alaninyl)amino]-2,3-dihydro-1-(3,3-acid dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-(Lancaster) oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-4573-[(N′-(2,6-difluoromandelyl)-L- 2,6-difluoromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 591.6 alaninyl)amino]-2,3-dihydro-1-(3,3-(Fluorochem) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4583-[(N′-(4-fluoromandelyl)-L- 4-fluoromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 573.6 alaninyl)amino]-2,3-dihydro-1-(3,3-(Lancaster) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4593-[(N′-(2,5-difluoromandelyl)-L- 2,5-difluoromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 591.6 alaninyl)amino]-2,3-dihydro-1-(3,3-(Fluorochem) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4603-[(N′-(2,4,6-trifluorophenylacetyl)- 2,4,6-trifluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 593.6 L-alaninyl)amino]-2,3-dihydro-1-acid dihydro-1-(3,3-dimethyl-2- (3,3-dimethyl-2-oxobutyl)-5-(2-(Fluorochem) oxobutyl)-5-(2-pyridyl)-1H-1,4-pyridyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example C-AG)8C-461 3-[(N′-(4-fluoro-2- 4-fluoro-2- 3-[(L-alaninyl)amino]-2,3- C-J625.6 (trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)dihydro-1-(3,3-dimethyl-2- alaninyl)amino]-2,3-dihydro-1-(3,3-phenylacetic acid oxobutyl)-5-(2-pyridyl)-1H-1,4-dimethyl-2-oxobutyl)-5-(2-pyridyl)- (Fluorochem) benzodiazepin-2-one1H-1,4-benzodiazepin-2-one (Example C-AG) 8C-4623-[(N′-(4,4,4-trifluorobutyryl)-L- 4,4,4-trifluorobutyric acid3-[(L-alaninyl)amino]-2,3- C-J 545.5 alaninyl)amino]-2,3-dihydro-1-(3,3-(Fluorochem) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4633-[(N′-(4-isopropylphenylacetyl)-L- 4-isopropylphenylacetic3-[(L-alaninyl)amino]-2,3- C-J 581.7 alaninyl)amino]-2,3-dihydro-1-(3,3-acid dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-(Lancaster) oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-464 3-[(N′-(beta-phenyllactyl)-L-beta-phenyllactic acid 3-[(L-alaninyl)amino]-2,3- C-J 569.6alaninyl)amino]-2,3-dihydro-1-(3,3- (Sigma) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4653-[(N′-(mandelyl)-L- mandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 555.6alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4663-[(N′-(4-chloromandelyl)-L- p-chloromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 590.1 alaninyl)amino]-2,3-dihydro-1-(3,3-(Acros) dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-467 3-[(N′-(isovaleryl)-L-isovaleric acid 3-[(L-alaninyl)amino]-2,3- C-J 505.6alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4683-[(N′-(2,3,5-trifluorophenylacetyl)- 2,3,5-trifluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 593.6 L-alaninyl)amino]-2,3-dihydro-1-acid dihydro-1-(3,3-dimethyl-2- (3,3-dimethyl-2-oxobutyl)-5-(2-(Fluorochem) oxobutyl)-5-(2-pyridyl)-1H-1,4-pyridyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example C-AG)8C-469 3-[(N′-(3-methylthiopropionyl)-L- 3-methylthiopropionic acid3-[(L-alaninyl)amino]-2,3- C-J 523.6 alaninyl)amino]-2,3-dihydro-1-(3,3-(Lancaster) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4703-[(N′-(L-alpha-hydroxyisocaproyl)-L- alpha-hydroxyisocaproic3-[(L-alaninyl)amino]-2,3- C-J 535.6 L-alaninyl)amino]-2,3-dihydro-1-acid dihydro-1-(3,3-dimethyl-2- (3,3-dimethyl-2-oxobutyl)-5-(2-(Aldrich) oxobutyl)-5-(2-pyridyl)-1H-1,4-pyridyl)-1H-1,4-benzodiazepin-2- benzodiazepin-2-one one (Example C-AG)8C-471 3-[(N′-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 584.6 alaninyl)amino]-2,3-dihydro-1-(3,3-(Aldrich) dihydro-1-(3,3-dimethyl-2- dimethyl-2-oxobutyl)-5-(2-pyridyl)-oxobutyl)-5-(2-pyridyl)-1H-1,4- 1H-1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AG) 8C-472 3-[(N′-(D-3-phenyllactyl)-L-D-3-phenyllactic acid 3-[(L-alaninyl)amino]-2,3- C-J 569.6alaninyl)amino]-2,3-dihydro-1-(3,3- (Aldrich) dihydro-1-(3,3-dimethyl-2-dimethyl-2-oxobutyl)-5-(2-pyridyl)- oxobutyl)-5-(2-pyridyl)-1H-1,4-1H-1,4-benzodiazepin-2-one benzodiazepin-2-one (Example C-AG) 8C-4733-[(N′-(4-methoxyphenylacetyl)-L- 4-Methoxyphenylacetic3-[(L-alaninyl)amino]-2,3- C-J 570.7 alaninyl)amino]-2,3-dihydro-1-(2-acid dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2- (Aldrich)aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4743-[(N′-(2-thiopheneacetyl)-L- 2-Thiopheneacetic acid3-[(L-alaninyl)amino]-2,3- C-J 546.7 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-475 3-[(N′-(N″-acetyl-N″-N-acetyl-N-phenylglycine 3-[(L-alaninyl)amino]-2,3- C-J 597.7phenylglycinyl)L-alaninyl)amino]- (Kodak) dihydro-1-(2-N,N-diethyl2,3-dihydro-1-(2-N,N-diethyl aminoethyl)-5-(2-pyridyl)-1H-aminoethyl)-5-(2-pyridyl)-1H-1,4- 1,4-benzodiazepin-2-onebenzodiazepin-2-one (Example C-AF) 8C-4763-[(N′-(3,5-difluorophenylacetyl)-L- 3,5-Difluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 576.6 alaninyl)amino]-2,3-dihydro-1-(2-acid dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2- (Aldrich)aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4773-[(N′-(3-bromophenylacetyl)-L- 3-Bromophenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 619.6 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4783-[(N′-(phenylmcercaptoacetyl)-L- Phenylmercaptoacetic acid3-[(L-alaninyl)amino]-2,3- C-J 572.7 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4793-[(N′-(4-ethoxyphenylacetyl)-L- 4-Ethoxyphenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 584.7 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-480 3-[(N′-(4- 4-3-[(L-alaninyl)amino]-2,3- C-J 608.7 (trifluoromethyl)phenylacetyl)-L-(trifluoromethyl)phenylacetic dihydro-1-(2-N,N-diethylalaninyl)amino]-2,3-dihydro-1-(2- acid aminoethyl)-5-(2-pyridyl)-1H-N,N-diethyl aminoethyl)-5-(2- (Aldrich) 1,4-benzodiazepin-2-onepyridyl)-1H-1,4-benzodiazepin-2- (Example C-AF) one 8C-481 3-[(N′-(3,5-3,5-Bis(trifluoromethyl) 3-[(L-alaninyl)amino]-2,3- C-J 676.7bis(trifluoromethyl)phenylacetyl)-L- phenylacetic aciddihydro-1-(2-N,N-diethyl alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich)aminoethyl)-5-(2-pyridyl)-1H- N,N-diethyl aminoethyl)-5-(2-1,4-benzodiazepin-2-one pyridyl)-1H-1,4-benzodiazepin-2- (Example C-AF)one 8C-482 3-[(N′-((methylthio)acetyl)-L- (methylthio)acetic acid3-[(L-alaninyl)amino]-2,3- C-J 510.6 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4833-[(N′-(cyclohexylacetyl)-L- cyclohexylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 546.7 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4843-[(N′-(pentafluorophenoxyacetyl)- pentafluorophenoxyacetic3-[(L-alaninyl)amino]-2,3- C-J 646.6 L-alaninyl)amino]-2,3-dihydro-1-(2-acid dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2- (Aldrich)aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4853-[(N′-(benzo[b]thiophene-3-acetyl)- benzo [b] thiophene-3-3-[(L-alaninyl)amino]-2,3- C-J 596.7 L-alaninyl)amino]-2,3-dihydro-1-(2-acetic acid dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-(Lancaster) aminoethyl)-5-(2-pyridyl)-1H-pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one (ExampleC-AF) 8C-486 3-[(N′-(benzoylformyl)-L- benzoylformic acid3-[(L-alaninyl)amino]-2,3- C-J 554.6 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-487 3-[(N′-(2,4,6-2,4,6-trimethylphenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 582.7trimethylphenyhlacetyl)-L- acid dihydro-1-(2-N,N-diethylalaninyl)amino]-2,3-dihydro-1-(2- (Lancaster)aminoethyl)-5-(2-pyridyl)-1H- N,N-diethyl aminoethyl)-5-(2-1,4-benzodiazepin-2-one pyridyl)-1H-1,4-benzodiazepin-2- (Example C-AF)one 8C-488 3-[(N′-(4-biphenylacetyl)-L- 4-biphenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 616.8 alaninyl)amino]-2,3-dihydro-1-(2-(Lancaster) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4893-[(N′-(3,4-difluorophenylacetyl)-L- 3,4-difluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 576.6 alaninyl)amino]-2,3-dihydro-1-(2-acid dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2- (Aldrich)aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4903-[(N′-(4-(2-thienyl)butyryl)-L- 4-(2-thienyl)butyric acid3-[(L-alaninyl)amino]-2,3- C-J 574.7 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4913-[(N′-(5-methylhexanoyl)-L- 5-methylhexanoic acid3-[(L-alaninyl)amino]-2,3- C-J 534.7 alaninyl)amino]-2,3-dihydro-1-(2-(P&B) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-492 3-[(N′-(3- mono-methylsuccinate 3-[(L-alaninyl)amino]-2,3- C-J 536.6methoxycarbonylpropionyl)-L- (Aldrich) dihydro-1-(2-N,N-diethylalaninyl)amino]-2,3-dihydro-1-(2- aminoethyl)-5-(2-pyridyl)-1H-N,N-diethyl aminoethyl)-5-(2- 1,4-benzodiazepin-2-onepyridyl)-1H-1,4-benzodiazepin-2- (Example C-AF) one 8C-4933-[(N′-(methanesulfonylacetyl)-L- methanesulfonylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 542.6 alaninyl)amino]-2,3-dihydro-1-(2-(Lancaster) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4943-[(N′-(4-toluenesulfonylacetyl)-L- 4-toluenesulfonylacetic3-[(L-alaninyl)amino]-2,3- C-J 618.7 alaninyl)amino]-2,3-dihydro-1-(2-acid dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2- (Lancaster)aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4953-[(N′-(2,6-difluoromandelyl)-L- 2,6-difluoromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 592.6 alaninyl)amino]-2,3-dihydro-1-(2-(Fluorochem) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4963-[N′-(4-fluoromandelyl)-L- 4-fluoromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 574.6 alaninyl)amino]-2,3-dihydro-1-(2-(Lancaster) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-4973-[(N′-(2,5-difluoromandelyl)-L- 2,5-difluoromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 592.6 alaninyl)amino]-2,3-dihydro-1-(2-(Fluorochem) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-498 3-[(N′-(4- 4-3-[(L-alaninyl)amino]-2,3- C-J 586.7 (hydroxymethyl)phenoxyacetyl)-L-(hydroxymethyl)phenoxyacetic dihydro-1-(2-N,N-diethylalaninyl)amino]-2,3-dihydro-1-(2- acid aminoethyl)-5-(2-pyridyl)-1H-N,N-diethyl aminoethyl)-5-(2- (Sigma) 1,4-benzodiazepin-2-onepyridyl)-1H-1,4-benzodiazepin-2- (Example C-AF) one 8C-4993-[(N′-(2,4,6-trifluorophenylacetyl)- 2,4,6-trifluorophenylacetic3-[(L-alaninyl)amino]-2,3- C-J 594.6 L-alaninyl)amino]-2,3-dihydro-1-(2-acid dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2- (Fluorochem)aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-500 3-[(N′-(4-fluoro-2-4-fluoro-2- 3-[(L-alaninyl)amino]-2,3- C-J 626.6(trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)dihydro-1-(2-N,N-diethyl alaninyl)amino]-2,3-dihydro-1-(2- phenylaceticacid aminoethyl)-5-(2-pyridyl)-1H- N,N-diethyl aminoethyl)-5-(2-(Fluorochem) 1,4-benzodiazepin-2-one pyridyl)-1H-1,4-benzodiazepin-2-(Example C-AF) one 8C-501 3-[(N′-(4,4,4-trifluorobutyryl)-L-4,4,4-trifluorobutyric acid 3-[(L-alaninyl)amino]-2,3- C-J 546.6alaninyl)amino]-2,3-dihydro-1-(2- (Fluorochem) dihydro-1-(2-N,N-diethylN,N-diethyl aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one (ExampleC-AF) 8C-502 3-[(N′-(4-isopropylphenylacetyl)-L- 4-isopropylphenylacetic3-[(L-alaninyl)amino]-2,3- C-J 582.7 alaninyl)amino]-2,3-dihydro-1-(2-acid dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2- (Lancaster)aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-5033-[(N′-(beta-phenyllactyl)-L- beta-phenyllactic acid3-[(L-alaninyl)amino]-2,3- C-J 570.7 alaninyl)amino]-2,3-dihydro-1-(2-(Sigma) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-504 3-[(N′-(mandelyl)-L-mandelic acid 3-[(L-alaninyl)amino]-2,3- C-J 556.7alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich) dihydro-1-(2-N,N-diethylN,N-diethyl aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one (ExampleC-AF) 8C-505 3-[(N′-(4-chloromandelyl)-L- p-chloromandelic acid3-[(L-alaninyl)amino]-2,3- C-J 591.1 alaninyl)amino]-2,3-dihydro-1-(2-(Acros) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-506 3-[(N′-(isovaleryl)-L-isovaleric acid 3-[(L-alaninyl)amino]-2,3- C-J 506.6alaninyl)amino]-2,3-dihydro-1-(2- (Aldrich) dihydro-1-(2-N,N-diethylN,N-diethyl aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one (ExampleC-AF) 8C-507 3-[(N′-(2,3,5-trifluorophenylacetyl)-2,3,5-trifluorophenylacetic 3-[(L-alaninyl)amino]-2,3- C-J 594.6L-alaninyl)amino]-2,3-dihydro-1-(2- acid dihydro-1-(2-N,N-diethylN,N-diethyl aminoethyl)-5-(2- (Fluorochem) aminoethyl)-5-(2-pyridyl)-1H-pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one (ExampleC-AF) 8C-508 3-[(N′-(3-methylthiopropionyl)-L- 3-methylthiopropionicacid 3-[(L-alaninyl)amino]-2,3- C-J 524.7alaninyl)amino]-2,3-dihydro-1-(2- (Lancaster) dihydro-1-(2-N,N-diethylN,N-diethyl aminoethyl)-5-(2- aminoethyl)-5-(2-pyridyl)-1H-pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one (ExampleC-AF) 8C-509 3-[(N′-(L-alpha-hydroxyisocaproyl)-L-alpha-hydroxyisocaproic 3-[(L-alaninyl)amino]-2,3- C-J 536.7L-alaninyl)amino]-2,3-dihydro-1-(2- acid dihydro-1-(2-N,N-diethylN,N-diethyl aminoethyl)-5-(2- (Aldrich) aminoethyl)-5-(2-pyridyl)-1H-pyridyl)-1H-1,4-benzodiazepin-2- 1,4-benzodiazepin-2-one one (ExampleC-AF) 8C-510 3-[(N′-(3-nitrophenylacetyl)-L- 3-nitrophenylacetic acid3-[(L-alaninyl)amino]-2,3- C-J 585.7 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF) 8C-5113-[(N′-(D-3-phenyllactyl)-L- D-3-phenyllactic acid3-[(L-alaninyl)amino]-2,3- C-J 570.7 alaninyl)amino]-2,3-dihydro-1-(2-(Aldrich) dihydro-1-(2-N,N-diethyl N,N-diethyl aminoethyl)-5-(2-aminoethyl)-5-(2-pyridyl)-1H- pyridyl)-1H-1,4-benzodiazepin-2-1,4-benzodiazepin-2-one one (Example C-AF)

General Procedure C-L

[2916] The following amino acids were employed in this procedure:L-alanine (Aldrich), L-valine (Aldrich), L-norvaline (Aldrich),L-methione (Aldrich), L-phenylalanine (Aldrich), L-(+)-α-phenylglycine(Aldrich), L-α-(2-thienyl)glycine (Sigma), L-α-(3-thienyl)glycine(Sigma), L-cyclohexylglycine hydrochloride (Senn Chemical AG),O-tert-butyl-L-serine (Sigma), O-tert-butyl-L-threonine (Bachem) andO-tert-butyl-L-tyrosine (Bachem).

[2917] The amino acid (60 μmoles), 305 mg (150 μmoles) ofN,O-bistrimethylsilylacetamaide and 1.5 mL of DMF were introduced intoseparate fritted screw capped vials. The mixtures were heated mildly andupon cooling 132 mg (15 μmoles) of p-nitrophenylcarbonate Wang resin(actual load of 1.14 mmole/g) (Novabiochem) was added to the individualvials. In addition, 73 mg (60 mmoles) of dimethylaminopyridine wasintroduced into vials containing L-cyclohexylglycine hydrochloride. Thevials were shaken at room temperature for 48 hours. Each reactionmixture was filtered through the internal frit and the resulting resinwas washed with (9×1.0 mL) of DMF, (9×1.0 mL) of methanol and (6×1.0 mL)of diethyl ether. Each reaction vial containing the resin bound aminoacid was then dried in a vacuum oven at 30° C.

General Procedure C-M

[2918] Into each fritted screw capped vial containing a resin boundamino acid (from General Procedure C-L) was introduced 81 mg (60 μmoles)of 1-hydroxybenzotriazole hydrate (HOBT H₂O), 115 mg (60 μmoles) of1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl),and 2 mL of THF. A3-amino-2,4-dioxo-1,5-bis-(alkyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin(30 μmoles) selected from3-amino-2,4-dioxo-1,5-bis(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin(Example 8S, Step C), 3-amino-2,4-dioxo-1,5-bis(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin (Example 8-R, Step C) and3-amino-2,4-dioxo-1,5-bis(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin(Example 8-U, Step C) was added to the vials. Each vial was then cappedand shaken at room temperature for 4 days. Each reaction mixture wasfiltered through the internal frit and the resulting resin was washedwith (3×2.0 mL) of DMF, (3×2.0 mL) of a 10% solution of acetic acid inmethanol, (3×2.0 mL) of a 10% solution of acetic acid in THF, and (3×2.0mL) of a 10% solution of acetic acid in dichloromethane.

General Procedure C-N

[2919] Each resin from General Procedure C-M was suspended in 2.0 mL oftrifluoroacetic acid for 30 minutes. Each reaction was filtered throughthe internal frit into a 10 mL vial and the resin was washed with (3×1.0mL) of methanol. The filtrate was concentrated under a flow of nitrogenat 30° C. The concentrated residue was dissolved in 1.5 mL of methanoland partitioned into 3 portions. Each portion was subjected to affinitychromatography on a pretreated SCX column (pretreatment consisted offlushing with 2 mL of a 10% solution of acetic acid in methanol followedby 2 mL of methanol). Once loaded, all columns were flushed with 5 nL ofmethanol, discarding each wash. Each compound was liberated from thecolumn with 5 mL of a 1 N solution of ammonia in a 1/1 solution ofmethanol and chloroform. Each solution was transferred to a tarred vialfollowed by concentration under a stream of nitrogen, followed by finalconcentration under vacuum.

General Procedure C-O

[2920] To each vial containing a specific amino acid benzodiazepine(from General Procedure C-N) was added 1 mL of a 0.4 M solution of1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (EDC) and 0.9 equivalentsof a carboxylic acid selected from 3,5-difluorophenylacetic acid,cyclopentylacetic acid and 4,4,4-trifluorophenylacetic acid. The vialswere capped and shaken for 4 days. Each reaction was then concentratedunder a continuous flow of nitrogen. The residue was subjected toaffinity chromatography on a pretreated SCX column (pretreatmentconsisted of flushing with 2 mL of a 10% solution of acetic acid inmethanol followed by 2 mL of methanol). Once loaded, all columns wereeluted with 5 mL of methanol. Each solution was transferred to a tarredvial followed by concentration under a stream of nitrogen with finalconcentration under vacuum.

[2921] Using the procedures indicated, the compounds shown in Table C-3were prepared. In this table, Starting Material 1 was prepared usingGeneral Procedures C-L, C-M and C-N. 3,5-Difluorophenylacetic acid andcyclopenylacetic acid are available from Aldrich, and4,4,4-trifluorobutyric acid is available from Fluorochem. TABLE C-3Example General No. Compound Starting Material 1 Starting Material 2Procedure MS 8C-512 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Alaninyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 529.2alaninyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2- Acid(2-methylpropyl)-2,3,4,5-tetrahydro- methylpropyl)-2,3,4,5-1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine 8C-5133-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Alaninyl)-amino-2,4-3,5-Difluorophenylacetic C-O 445.1 alaninyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(methyl)- Acid (methyl)-2,3,4,5-tetrahydro-1H-1,5-2,3,4,5-tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-5143-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Alaninyl)-amino-2,4-3,5-Difluorophenylacetic C-O 525.2 alaninyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis- Acid (cyclopropylmethyl)-2,3,4,5- (cyclopropylmethyl)-tetrahydro-1H-1,5-benzodiazepine 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 8C-515 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Valinyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 557.3valinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2- Acid(2-methylpropyl)-2,3,4,5-tetrahydro- methylpropyl)-2,3,4,5-1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine 8C-5163-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Valinyl)-amino-2,4-3,5-Difluorophenylacetic C-O 473.2 valinyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(methyl)- Acid (methyl)-2,3,4,5-tetrahydro-1H-1,5-2,3,4,5-tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-5173-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Valinyl)-amino-2,4-3,5-Difluorophenylacetic C-O 553.2 valinyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(cyclopropyl- Acid (cyclopropylmethyl)-2,3,4,5-methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-518 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Norvalinyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 557.3norvalinyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl- Acidbis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5193-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Norvalinyl)-amino-2,4-3,5-Difluorophenylacetic C-O 473.2 norvalinyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(methyl)- Acid bis-(methyl)-2,3,4,5-tetrahydro-1H-2,3,4,5-tetrahydro-1H-1,5- 1,5-benzodiazepine benzodiazepine 8C-5203-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Norvalinyl)-amino-2,4-3,5-Difluorophenylacetic C-O 553.2 norvalinyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(cyclopropyl- Acid bis-(cyclopropylmethyl)-2,3,4,5-methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-521 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Methioninyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 587.3methioninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl- Acidbis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5223-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Methioninyl)-amino-2,4-3,5-Difluorophenylacetic C-O 503.2 methioninyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(methyl)- Acid bis-(methyl)-2,3,4,5-tetrahydro-1H-2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine 1,5-benzodiazepine 8C-5233-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Methioninyl)-amino-2,4-3,5-Difluorophenylacetic C-O 583.2 methioninyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(cyclopropyl- Acid bis-(cyclopropylmethyl)-2,3,4,5-methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-524 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Phenylalaninyl)-amino- 3,5-Difluorophenylacetic C-O 603.3phenylalaninyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl- Acid1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5253-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Phenylalaninyl)-amino-3,5-Difluorophenylacetic C-O 519.2 phenylalaninyl]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(methyl)- Acid 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine1,5-benzodiazepine 8C-526 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Phenylalaninyl)-amino- 3,5-Difluorophenylacetic C-O 601.2phenylalaninyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo- Acid1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepinebenzodiazepine 8C-527 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Phenylglycinyl)-amino- 3,5-Difluorophenylacetic C-O 591.3phenylglycinyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl- Acid1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5283-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Phenylglycinyl)-amino-3,5-Difluorophenylacetic C-O 507.2 phenylglycinyl]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(methyl)- Acid 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine1,5-benzodiazepine 8C-529 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Phenylglycinyl)-amino- 3,5-Difluorophenylacetic C-O 587.2phenylglycinyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo- Acid1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepinebenzodiazepine 8C-530 3-[N-(3,5-Difluorophenylacetyl)-(2-3-[(2-Thienyl)glycine]-amino- 3,5-Difluorophenylacetic C-O 597.2thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl- Acid1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5313-[N-(3,5-Difluorophenylacetyl)-(2- 3-[(2-Thienyl)glycine]-amino-3,5-Difluorophenylacetic C-O 513.1 thienyl)glycine]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(methyl)- Acid 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine1,5-benzodiazepine 8C-532 3-[N-(3,5-Difluorophenylacetyl)-(2-3-[(2-Thienyl)glycine]-amino- 3,5-Difluorophenylacetic C-O 593.2thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis- Acid1,5-bis-(cyclopropylmethyl)- (cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5- 2,3,4,5-tetrahydro-1H- benzodiazepine1,5-benzodiazepine 8C-533 3-[N-(3,5-Difluorophenylacetyl)-(3-3-[(3-Thienyl)glycine]-amino- 3,5-Difluorophenylacetic C-O 597.2thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl- Acid1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5343-[N-(3,5-Difluorophenylacetyl)-(3- 3-[(3-Thienyl)glycine]-amino-3,5-Difluorophenylacetic C-O 513.1 thienyl)glycine]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(methyl)- Acid 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine1,5-benzodiazepine 8C-535 3-[N-(3,5-Difluorophenylacetyl)-(3-3-[(3-Thienyl)glycine]-amino- 3,5-Difluorophenylacetic C-O 593.2thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo- Acid1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepinebenzodiazepine 8C-536 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Threoninyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 559.3threoninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl- Acidbis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5373-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Threoninyl)-amino-2,4-3,5-Difluorophenylacetic C-O 475.2 threoninyl]-amino-2,4-dioxo-dioxo-1,5-bis-(methyl)- Acid 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine1,5-benzodiazepine 8C-538 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Threoninyl)-amino- 3,5-Difluorophenylacetic C-O 555.2threoninyl]-amino-2,4-dioxo-1,5- 2,4-dioxo-1,5-bis-(cyclo- Acidbis-(cyclopropylmethyl)-2,3,4,5- propylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine8C-539 3-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Tyrosinyl)-amino-2,4-3,5-Difluorophenylacetic C-O 621.3 tyrosinyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(2-methyl- Acid (2-methylpropyl)-2,3,4,5-propyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-540 3-[N-(3,5-Difluorophenylacetyl)-L-3-(L-Tyrosinyl)-amino-2,4- 3,5-Difluorophenylacetic C-O 537.2tyrosinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(methyl)- Acid(methyl)-2,3,4,5-tetrahydro-1H- 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-5413-[N-(3,5-Difluorophenylacetyl)-L- 3-(L-Tyrosinyl)-amino-2,4-3,5-Difluorophenylacetic C-O 617.3 tyrosinyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(cyclopropyl- Acid bis-(cyclopropylmethyl)-2,3,4,5-methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-542 3-[N-(Cyclopentylacetyl)-L-3-(L-Alaninyl)-amino-2,4- Cyclopentylacetic Acid C-O 485.3alaninyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2-methyl-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5433-[N-(Cyclopentylacetyl)-L- 3-(L-Alaninyl)-amino-2,4- CyclopentylaceticAcid C-O 401.2 alaninyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(methyl)- (methyl)-2,3,4,5-tetrahydro-1H-2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine 1,5-benzodiazepine 8C-5443-[N-(Cyclopentylacetyl)-L- 3-(L-Alaninyl)-amino-2,4- CyclopentylaceticAcid C-O 481.3 alaninyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(cyclopropyl- (cyclopropylmethyl)-2,3,4,5-methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-545 3-[N-(Cyclopentylacetyl)-L-3-(L-Valinyl)-amino-2,4- Cyclopentylacetic Acid C-O 513.3valinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2-methyl-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5463-[N-(Cyclopentylacetyl)-L- 3-(L-Valinyl)-amino-2,4- CyclopentylaceticAcid C-O 429.2 valinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(methyl)-(methyl)-2,3,4,5-tetrahydro-1H- 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-547 3-[N-(Cyclopentylacetyl)-L-3-(L-Valinyl)-amino-2,4- Cyclopentylacetic Acid C-O 509.3valinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(cyclopropyl-(cyclopropylmethyl)-2,3,4,5- methyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5483-[N-(Cyclopentylacetyl)-L- 3-(L-Norvalinyl)-amino-2,4-Cyclopentylacetic Acid C-O 513.3 norvalinyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(2-methyl- bis-(2-methylpropyl)-2,3,4,5-propyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-549 3-[N-(Cyclopentylacetyl)-L-3-(L-Norvalinyl)-amino-2,4- Cyclopentylacetic Acid C-O 429.2norvalinyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(methyl)-bis-(methyl)-2,3,4,5-tetrahydro-1H- 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-550 3-[N-(Cyclopentylacetyl)-L-3-(L-Norvalinyl)-amino-2,4- Cyclopentylacetic Acid C-O 509.3norvalinyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(cyclopropyl-bis-(cyclopropylmethyl)-2,3,4,5- methyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5513-[N-(Cyclopentylacetyl)-L- 3-(L-Methioninyl)-amino-2,4-Cyclopentylacetic Acid C-O 545.3 methioninyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(2-methyl- bis-(2-methylpropyl)-2,3,4,5-propyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-552 3-[N-(Cyclopentylacetyl)-L-3-(L-Methioninyl)-amino-2,4- Cyclopentylacetic Acid C-O 461.2methioninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(methyl)-bis-(methyl)-2,3,4,5-tetrahydro-1H- 2,3,4,5-tetrahydro-1H1,5-benzodiazepine 1,5-benzodiazepine 8C-553 3-[N-(Cyclopentylacetyl)-L-3-(L-Methioninyl)-amino-2,4- Cyclopentylacetic Acid C-O 541.3methioninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(cyclopropyl-bis-(cyclopropylmethyl)-2,3,4,5- methyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5543-[N-(Cyclopentylacetyl)-L- 3-(L-Phenylalaninyl)-amino-Cyclopentylacetic Acid C-O 561.3 phenylalaninyl]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(2-methyl- 1,5-bis-(2-methylpropyl)-2,3,4,5-propyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-555 3-[N-(Cyclopentylacetyl)-L-3-(L-Phenylalaninyl)-amino- Cyclopentylacetic Acid C-O 477.2phenylalaninyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(methyl)-1,5-bis-(methyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-tetrahydro-1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-5563-[N-(Cyclopentylacetyl)-L- 3-(L-Phenylalaninyl)-amino-Cyclopentylacetic Acid C-O 557.3 phenylalaninyl]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(cyclo- 1,5-bis-(cyclopropylmethyl)-propylmethyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepine benzodiazepine 8C-557 3-[N-(Cyclopentylacetyl)-L-3-(L-Phenylglycinyl)-amino- Cyclopentylacetic Acid C-O 547.3phenylglycinyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-1,5-bis-(2-methylpropyl)-2,3,4,5- methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine8C-558 3-(N-(Cyclopentylacetyl)-L- 3-(L-Phenylglycinyl)-amino-Cyclopentylacetic Acid C-O 463.2 phenylglycinyl]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine1,5-benzodiazepine 8C-559 3-[N-(Cyclopentylacetyl)-L-3-(L-Phenylglycinyl)-amino- Cyclopentylacetic Acid C-O 543.3phenylglycinyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo-1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepinebenzodiazepine 8C-560 3-[N-(Cyclopentylacetyl)-(2-3-[(2-Thienyl)glycine]-amino- Cyclopentylacetic Acid C-O 551.3thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl-1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5613-[N-(Cyclopentylacetyl)-(2- 3-[(2-Thienyl)glycine]-amino-Cyclopentylacetic Acid C-O 469.2 thienyl)glycine]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine1,5-benzodiazepine 8C-562 3-[N-(Cyclopentylacetyl)-(2-3-[(2-Thienyl)glycine]-amino- Cyclopentylacetic Acid C-O 549.2thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo-1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepinebenzodiazepine 8C-563 3-[N-(Cyclopentylacetyl)-(3-3-[(3-Thienyl)glycine]-amino- Cyclopentylacetic Acid C-O 553.3thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl-1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5643-[N-(Cyclopentylacetyl)-(3- 3-[(3-Thienyl)glycine]-amino-Cyclopentylacetic Acid C-O 469.2 thienyl)glycine]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H- tetrahydro-1H-1,5-benzodiazepine1,5-benzodiazepine 8C-565 3-[N-(Cyclopentylacetyl)-(3-3-[(3-Thienyl)glycine]-amino- Cyclopentylacetic Acid C-O 549.2thienyl)glycine]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo-1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepinebenzodiazepine 8C-566 3-[N-(Cyclopentylacetyl)-L-3-(L-Serinyl)-amino-2,4- Cyclopentylacetic Acid C-O 417.2serinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2-methyl-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5673-[N-(Cyclopentylacetyl)-L- 3-(L-Threoninyl)-amino-2,4-Cyclopentylacetic Acid C-O 515.3 threoninyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(2-methyl- bis-(2-methylpropyl)-2,3,4,5-propyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-568 3-[N-(Cyclopentylacetyl)-L-3-(L-Threoninyl)-amino-2,4- Cyclopentylacetic Acid C-O 431.2threoninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(methyl)-2,3,4,5-bis-(methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-1H-1,5-benzodiazepine benzodiazepine 8C-569 3-[N-(Cyclopentylacetyl)-L-3-(L-Threoninyl)-amino-2,4- Cyclopentylacetic Acid C-O 511.3threoninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(cyclopropyl-bis-(cyclopropylmethyl)-2,3,4,5- methyl)-2,3,4,5-tetrahydro-1H-tetrahydro-1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-5703-[N-(Cyclopentylacetyl)-L- 3-(L-Tyrosinyl)-amino-2,4- CyclopentylaceticAcid C-O 577.3 tyrosinyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(2-methyl- (2-methylpropyl)-2,3,4,5-propyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-571 3-[N-(Cyclopentylacetyl)-L-3-(L-Tyrosinyl)-amino-2,4- Cyclopentylacetic Acid C-O 493.2tyrosinyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(methyl)-bis-(methyl)-2,3,4,5-tetrahydro- 2,3,4,5-tetrahydro-1H-1,5-1H-1,5-benzodiazepine benzodiazepine 8C-572 3-[N-(Cyclopentylacetyl)-L-3-(L-Tyrosinyl)-amino-2,4- Cyclopentylacetic Acid C-O 573.3tyrosinyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(cyclopropyl-bis-(cyclopropylmethyl)-2,3,4,5- methyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5733-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Alaninyl)-amino-2,4-4,4,4-Trifluorobutyric Acid C-O 499.2 alaninyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(2-methyl- (2-methylpropyl)-2,3,4,5-propyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-574 3-[N-(4,4,4-Trifluorobutryl)-L-3-(L-Alaninyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-O 415.1alaninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(methyl)-bis-(methyl)-2,3,4,5-tetrahydro- 2,3,4,5-tetrahydro-1H-1,5-1H-1,5-benzodiazepine benzodiazepine 8C-5753-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Alaninyl)-amino-2,4-4,4,4-Trifluorobutyric Acid C-O 495.2 alaninyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(cyclopropyl- (cyclopropylmethyl)-2,3,4,5-methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-576 3-[N-(4,4,4-Trifluorobutryl)-L-3-(L-Valinyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-O 527.3valinyl]-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(2-methyl-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5773-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Valinyl)-amino-2,4-4,4,4-Trifluorobutyric Acid C-O 443.2 valinyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(methyl)- (methyl)-2,3,4,5-tetrahydro-1H-2,3,4,5-tetrahydro-1H-1,5- 1,5-benzodiazepine benzodiazepine 8C-5783-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Valinyl)-amino-2,4-4,4,4-Trifluorobutyric Acid C-O 523.2 valinyl]-amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(cyclopropyl- (cyclopropylmethyl)-2,3,4,5-methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-579 3-[N-(4,4,4-Trifluorobutryl)-L-3-(L-Norvalinyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-O 527.3norvalinyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methyl-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5803-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Norvalinyl)-amino-2,4-4,4,4-Trifluorobutyric Acid C-O 443.2 norvalinyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(methyl)- bis-(methyl)-2,3,4,5-tetrahydro-2,3,4,5-tetrahydro-1H- 1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-5813-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Norvalinyl)-amino-2,4-4,4,4-Trifluorobutyric Acid C-O 523.2 norvalinyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(cyclopropyl- bis-(cyclopropylmethyl)-2,3,4,5-methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-582 3-[N-(4,4,4-Trifluorobutryl)-L-3-(L-Methioninyl)-amino-2,4- 4,4,4-Trifluorobutyric Acid C-O 559.2methioninyl]-amino-2,4-dioxo-1,5- dioxo-1,5-bis-(2-methylpropyl)-bis-(2-methylpropyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-tetrahydro-1H-1,5-benzodiazepine 1,5-benzodiazepine 8C-5833-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Methioninyl)-amino-2,4-4,4,4-Trifluorobutyric Acid C-O 475.1 methioninyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(methyl)- bis-(methyl)-2,3,4,5-tetrahydro-2,3,4,5-tetrahydro-1H-1,5- 1H-1,5-benzodiazepine benzodiazepine 8C-5843-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Methioninyl)-amino-2,4-4,4,4-Trifluorobutyric Acid C-O 555.2 methioninyl]-amino-2,4-dioxo-1,5-dioxo-1,5-bis-(cyclopropyl- bis-(cyclopropylmethyl)-2,3,4,5-methyl)-2,3,4,5-tetrahydro- tetrahydro-1H-1,5-benzodiazepine1H-1,5-benzodiazepine 8C-585 3-[N-(4,4,4-Trifluorobutryl)-L-3-(L-Phenylalaninyl)-amino- 4,4,4-Trifluorobutyric Acid C-O 475.3phenylalaninyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-methyl-1,5-bis-(2-methylpropyl)-2,3,4,5- propyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5863-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Phenylalaninyl)-amino-4,4,4-Trifluorobutyric Acid C-O 491.2 phenylalaninyl]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepinebenzodiazepine 8C-587 3-[N-(4,4,4-Trifluorobutryl)-L-3-(L-Phenylalaninyl)-amino- 4,4,4-Trifluorobutyric Acid C-O 571.2phenylalaninyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(cyclo-1,5-bis-(cyclopropylmethyl)- propylmethyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepinebenzodiazepine 8C-588 3-[N-(4,4,4-Trifluorobutryl)-3-(Phenylglycinyl)-amino- 4,4,4-Trifluorobutyric Acid C-O 561.2phenylglycinyl]-amino-2,4-dioxo- 2,4-dioxo-1,5-bis-(2-1,5-bis-(2-methylpropyl)-2,3,4,5- methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine tetrahydro-1H-1,5- benzodiazepine8C-589 3-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Phenylglycinyl)-amino-4,4,4-Trifluorobutyric Acid C-O 477.1 phenylglycinyl]-amino-2,4-dioxo-2,4-dioxo-1,5-bis-(methyl)- 1,5-bis-(methyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepinebenzodiazepine 8C-590 3-[N-(4,4,4-Trifluorobutryl)-L-3-[L-(2-Thienyl)glycine]- 4,4,4-Trifluorobutyric Acid C-O 567.2(2-thienyl)glycine]-amino-2,4- amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(2-methylpropyl)- (2-methylpropyl)-2,3,4,5-2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5- benzodiazepinebenzodiazepine 8C-591 3-[N-(4,4,4-Trifluorobutryl)-L-3-[L-(2-Thienyl)glycine]- 4,4,4-Trifluorobutyric Acid C-O 483.1(2-thienyl)glycine]-amino-2,4- amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(methyl)-2,3,4,5- (methyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5923-[N-(4,4,4-Trifluorobutryl)-L- 3-[L-(2-Thienyl)glycine]-4,4,4-Trifluorobutyric Acid C-O 563.2 (2-thienyl)glycine]-amino-2,4-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(cyclopropylmethyl)-(cyclopropylmethyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5-tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-5933-[N-(4,4,4-Trifluorobutryl)-L- 3-[L-(3-Thienyl)glycine]-4,4,4-Trifluorobutyric Acid C-O 567.2 (3-thienyl)glycine]-amino-2,4-amino-2,4-dioxo-1,5-bis-(2- dioxo-1,5-bis-(2-methylpropyl)-methylpropyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepine benzodiazepine 8C-594 3-[N-(4,4,4-Trifluorobutryl)-L-3-[L-(3-Thienyl)glycine]- 4,4,4-Trifluorobutyric Acid C-O 483.1(3-thienyl)glycine]-amino-2,4- amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(methyl)-2,3,4,5- (methyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5953-[N-(4,4,4-Trifluorobutryl)-L- 3-[L-(3-Thienyl)glycine]-4,4,4-Trifluorobutyric Acid C-O 563.2 (3-thienyl)glycine]-amino-2,4-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(cyclopropylmethyl)-(cyclopropylmethyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5-tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-5963-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)-4,4,4-Trifluorobutyric Acid C-O 567.3 cyclohexylglycinyl]-amino-2,4-amino-2,4-dioxo-1,5-bis-(2- dioxo-1,5-bis-(2-methylpropyl)-methylpropyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5- tetrahydro-1H-1,5-benzodiazepine benzodiazepine 8C-597 3-[N-(4,4,4-Trifluorobutryl)-L-3-(L-Cyclohexylglycinyl)- 4,4,4-Trifluorobutyric Acid C-O 483.2cyclohexylglycinyl]-amino-2,4- amino-2,4-dioxo-1,5-bis-dioxo-1,5-bis-(methyl)-2,3,4,5- (methyl)-2,3,4,5-tetrahydro-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-5983-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)-4,4,4-Trifluorobutyric Acid C-O 563.3 cyclohexylglycinyl]-amino-2,4-amino-2,4-dioxo-1,5-bis- dioxo-1,5-bis-(cyclopropylmethyl)-(cyclopropylmethyl)-2,3,4,5- 2,3,4,5-tetrahydro-1H-1,5-tetrahydro-1H-1,5- benzodiazepine benzodiazepine 8C-5993-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)-4,4,4-Trifluorobutyric Acid C-O 527.3 threoninyl]-amino-2,4-dioxo-1,5-amino-2,4-dioxo-1,5-bis- bis-(2-methylpropyl)-2,3,4,5-(2-methylpropyl)-2,3,4,5- tetrahydro-1H-1,5-benzodiazepinetetrahydro-1H-1,5- benzodiazepine 8C-600 3-[N-(4,4,4-Trifluorobutryl)-3-(L-Cyclohexylglycinyl)- 4,4,4-Trifluorobutyric Acid C-O 445.2threoninyl]-amino-2,4-dioxo-1,5- amino-2,4-dioxo-1,5-bis-bis-(methyl)-2,3,4,5-tetrahydro- (methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine 1H-1,5-benzodiazepine 8C-6013-[N-(4,4,4-Trifluorobutryl)-L- 3-(L-Cyclohexylglycinyl)-4,4,4-Trifluorobutyric Acid C-O 525.2 threoninyl]-amino-2,4-dioxo-1,5-amino-2,4-dioxo-1,5-bis- bis-(cyclopropylmethyl)-2,3,4,5-(cyclopropylmethyl)-2,3,4,5- tetrahydro-1H-1,5-benzodiazepinetetrahydro-1H-1,5- benzodiazepine

General Procedure C-P

[2922] A solution of the carboxylic acid (0.75 mL, 0.05 M in DCM) wasreacted withL-alaninyl-5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (0.75mL, 0.06 M in DCM) (from Example 7-I), PP-HOBT (0.3 mL, 0.15 M in DMF,this reagent was used only with alpha substituted carboxylic acids), andEDC (0.3 mL, 0.15 M). The reaction was mixed for 18 hours, then purifiedon a Varian SCX column (500 mg column prewashed with MeOH (3×2.5 mL) and20% MeOH:DCM (3×2.5 mL)) eluting with 2.5 mL of 20% MeOH:DCM.

General Procedure C-Q

[2923] Step A: FMOC-Gly Wang resin (20 g, 10.8 mmole, NovabiochemA16415) was reacted with a 30% solution of piperidine inN-methylpyrrolidinone (NMP) for 30 minutes. The solution was drained andthe resin washed with NMP (5×200 mL). Benzophenone imine (19.5 g, 108mmole) in NMP (150 mL) was added to the resin followed by glacial aceticacid (5.6 g, 94 mmole) and the reaction was mixed overnight at roomtemperature. Reagents were drained and the resin washed with NMP (5×150mL) followed by DCM (5×150 mL). The resin was dried under vacuum toafford (benzophenone imine)-Gly Wang resin with a theoretical loading of0.56 mmole per gram.

[2924] Step B: A suspension of the resin from Step A in NMP (9 mL) wasreacted with an alkyl bromide (5.6 mL of 1 M solution in NMP) selectedfrom 1-bromo-2-ethylbutane, 1-bromo-3-methylbutane, cyclopropylmethylbromide, 1-bromo-2-cyclohexylethane, 1-bromo4-fluorobutane, and1-bromo-2-methylbutane; and BEMP (5.6 mL of 1 M solution in NMP) andBu₄NI (5.6 mL of 1 M solution in NMP) for 20 hours at room temperature.Reagents were drained and the resin washed with NMP (3×15 mL). To amixture of the resin in THF (7 mL) was added hydroxylamine hydrochloride(2 mL of a 1.6 M solution in water) and the reaction was mixed for 20hours at room temperature. Reagents were drained and the resin washedsequentially with THF (2×5 mL), 0.5 M solution of diisopropylethylaminein THF (5 mL), THF (5 mL), and NMP (3×5 mL).

[2925] Step C: The resin from Step B was divided into 12 equal reactionsusing an isopicnic solution in NMP:CH₂Cl₂. To each reaction was addedsequentially a carboxylic acid (0.75 mL of a 0.45 M solution in NMP),HOBT (0.75 mL of a 0.45 M solution in NMP) and DIC (0.75 mL of a 0.45 Msolution in NMP). The reaction was mixed for 18 hours at roomtemperature. Reagents were drained and the resin washed with NMP (5×0.5mL), and DCM (5×0.5 mL). The resin was mixed with TFA:H₂O (95:5, 0.5 mL)for 4 hours. The filtrate was collected, resin washed with TFA:H₂O(95:5, 0.5 mL) and the filtrates combined. Solvents were evaporated toyield the N-acyl amino acid.

General Procedure C-R

[2926] Various acylated amino acids (approximately 0.02 mmole) (fromGeneral Procedure C-Q) in separate vials were reacted with5-amino-7-methyl-5,7-dihydro-6H-dibenz[bd]azepin-6-one (0.1 mL, 0.3 M inDCM) (Example 7-A), PP-HOBT (0.2 mL, 0.15 M in DMF), and EDC-HCl (0.4mL, 0.08 M in DCM). Reactions were mixed for 18 hours at roomtemperature. Reactions were diluted with 0.5 mL MeOH, loaded onto aVarian SCX column (500 mg, Varian Sample Preparations, pre-washed withMeOH (2.5 mL) and 10% MeOH:CHCl₃ (2.5 mL)), and eluted with 10%MeOH:CHCl₃ (2.5 mL). Solvents were evaporated from the products and thecrude products purified by semi-prep reverse phase chromatography(gradient 0 to 100%, 0.1% TFA in H₂O to 0.08% TFA in CH₃CN). The correctmolecular ion was detected for each product by ionspray mass spec andanalytical reverse phase chromatography (gradient 0 to 100%, 0.01% TFAin H₂O to 0.08% TFA in CH3CN) showed the products to be greater than 90%pure.

[2927] Using the procedures indicated, the compounds shown in Table C-4were prepared. In this table, starting material 2 was prepared asdescribed in Example 7-I. TABLE C-4 Example General No. CompoundStarting Material 1 Starting Material 2 Procedure MS 7C-15-{N′-(Cyclopentyl acetyl)-L- Cyclopentyl acetic acid5-(L-alaninyl)-amino-7- C-P 420.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-2 5-{N′-(3-cyclopentylpropionyl)-L-3-cyclopentylpropionic 5-(L-alaninyl)-amino-7- C-P 434.2alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-3 5-{N′-(cyclohexylacetyl)-L- cyclohexylacetic acid5-(L-alaninyl)-amino-7- C-P 434.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-4 5-{N′-(t-butylacetyl)-L-alaninyl}-t-butylacetic acid 5-(L-alaninyl)-amino-7- C-P 408.2amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-55-{N′-(phenylacetyl)-L-alaninyl}- phenylacetic acid5-(L-alaninyl)-amino-7- C-P 428.2 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-6 5-{N′-(3-bromophenylacetyl)-L-3-bromophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 506.0,alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H- 508.0dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-75-{N′-(3-fluorophenylacetyl)-L- 3-fluorophenylacetic acid5-(L-alaninyl)-amino-7- C-P 446.0 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-8 5-{N′-(3-chlorophenylacetyl)-L-3-chlorophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 462.2alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-95-{N′-(3- 3- 5-(L-alaninyl)-amino-7- C-P 496.0(trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenyl-methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acetic aciddibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Marshallton)one 7C-10 5-{N′-(4-fluorophenylacetyl)-L- 4-fluorophenylacetic acid5-(L-alaninyl)-amino-7- C-P 446.0 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-11 5-{N′-(hexanoyl)-L-alaninyl}- hexanoicacid 5-(L-alaninyl)-amino-7- C-P 408.2 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-12 5-{N′-(heptanoyl)-L-alaninyl}- heptanoicacid 5-(L-alaninyl)-amino-7- C-P 422.2 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-13 5-{3,4-difluorophenylacetyl)-L-3,4-difluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 464.2alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-14 5-{N′-(cyclopropylacetyl)-L- cyclopropylacetic acid5-(L-alaninyl)-amino-7- C-P 392.2 alaninyl}-amino-7-methyl-5,7-(Lancaster) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-15 5-{N′-(2-cyclopentene-1-acetyl)-L-2-cyclopentene-1-acetic 5-(L-alaninyl)-amino-7- C-P 418.2alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-16 5-{N′-(3-cyclohexylpropionyl)-L- 3-cyclohexylpropionic acid5-(L-alaninyl)-amino-7- C-P 448.0 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-17 5-{N′-(isovaleryl)-L-alaninyl}-isovaleric acid 5-(L-alaninyl)-amino-7- C-P 394.0amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-185-{N′-(citronellyl)-L-alaninyl}- citronellic acid5-(L-alaninyl)-amino-7- C-P 462.2 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-19 5-{N′-(3-benzoylpropionyl)-L-3-benzoylpropionic acid 5-(L-alaninyl)-amino-7- C-P 470.2alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-205-{N′-(2-chlorophenylacetyl)-L- 2-chlorophenylacetic acid5-(L-alaninyl)-amino-7- C-P 462.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-21 5-{N′-(4-pentenoyl)-L-alaninyl}-4-pentenoic acid 5-(L-alaninyl)-amino-7- C-P 392.0amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-225-{N′-(valeryl)-L-alaninyl}-amino- valeric acid 5-(L-alaninyl)-amino-7-C-P 394.0 7-methyl-5,7-dihydro-6H- (Eastman) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz [b,d]azepin-6-one 7C-235-{N′-(2-thiophenecetyl)-L- 2-thiophenecetic acid5-(L-alaninyl)-amino-7- C-P 434.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-24 5-{N′-(4-(2-thienyl)butyryl)-L-4-(2-thienyl)butyric acid 5-(L-alaninyl)-amino-7- C-P 462.2alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-255-{N′-(4-(4-nitrophenyl)butyryl)-L- 4-(4-nitrophenyl)butyric5-(L-alaninyl)-amino-7- C-P 501.0 alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)dibenz[b,d]azepin-6-one one 7C-26 5-{N′-(2,4-difluorophenylacetyl)-L-2,4-difluorophenylacetic 5-(L-alaninyl)-amino-7- C-P 464.2alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-27 5-{N′-(2,6-difluorophenylacetyl)-L- 2,6-difluorophenylacetic5-(L-alaninyl)-amino-7- C-P 464.2 alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)dibenz[b,d]azepin-6-one one 7C-28 5-{N′-(4-isopropylphenylacetyl)-L-4-isopropylphenylacetic 5-(L-alaninyl)-amino-7- C-P 470.2alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) dibenz[b,d]azepin-6-one one7C-29 5-{N′-(1-adamantaneacetyl)-L- 1-adamantaneacetic acid5-(L-alaninyl)-amino-7- C-P 486.4 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-30 5-{N′-(cyclohexanepentanoyl)-L-cyclohexanepentanoic acid 5-(L-alaninyl)-amino-7- C-P 476.2alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-315-{N′-((methylthio)acetyl)-L- (methylthio)acetic acid5-(L-alaninyl)-amino-7- C-P 398.0 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-32 5-{N′-(2-thiophenepentanoyl)-L-2-thiophenepentanoic acid 5-(L-alaninyl)-amino-7- C-P 476.0alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-335-{N′-(2-norbornaneacetyl)-L- 2-norbornaneacetic acid5-(L-alaninyl)-amino-7- C-P 446.0 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-34 5-{N′-(3,5-difluorophenylacetyl)-4-(3,5-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 534.2ethylnorleucinyl}-amino-7-methyl- 4-ethylnorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-35 5-{N′-(3,5-difluorophenylacetyl)-4-(3,5-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 520.2methylnorleucinyl}-amino-7- 4-methylnorleucine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-36 5-{N′-(3,5-difluorophenylacetyl)-3-(3,5-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 504.0cyclopropylalaninyl}-amino-7- 3-cyclopropylalanine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-37 5-{N′-(3,5-difluorophenylacetyl)-4-(3,5-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 560.2cyclohexylhomoalaninyl}-amino-7- 4-cyclohexylhomoalanine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-38 5-{N′-(3,5-difluorophenylacetyl)-6-(3,5-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 524.0fluoronorleucinyl}-amino-7-methyl- 6-fluoronorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-39 5-{N′-(3,5-difluorophenylacetyl)-4-(3,5-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 520.0methylnorleucinyl}-amino-7- 4-methylnorleucine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-40 5-{N′-(cyclohexylacetyl)-4-(cyclohexylacetyl)-4- 5-amino-7-methyl-5,7- C-R 504.3ethylnorleucinyl}-amino-7-methyl- ethylnorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-41 5-{N′-(cyclopropylacetyl)-4-(cyclopropylacetyl)-4- 5-amino-7-methyl-5,7- C-R 462.3ethylnorleucinyl}-amino-7-methyl- ethylnorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-42 5-{N′-(isovaleryl)-4- (isovaleryl)-4-5-amino-7-methyl-5,7- C-R 464.3 ethylnorleucinyl}-amino-7-methyl-ethylnorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin- (GeneralProcedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-43 5-{N′-(3- (3-5-amino-7-methyl-5,7- C-R 566.3 (trifluoromethyl)phenylacetyl)-4-(trifluoromethyl)phenyl- dihydro-6H- ethylnorleucinyl}-amino-7-methyl-acetyl)-4-ethylnorleucine dibenz[bd]azepin-6-one5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q) 6-one 7C-445-{N′-(3,4-difluorophenylacetyl)-4- (3,4-difluorophenylacetyl)-5-amino-7-methyl-5,7- C-R 534.3 ethylnorleucinyl}-amino-7-methyl-4-ethylnorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin- (GeneralProcedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-455-{N′-(2,4-difluorophenylacetyl)-4- (2,4-difluorophenylacetyl)-5-amino-7-methyl-5,7- C-R 534.3 ethylnorleucinyl}-amino-7-methyl-4-ethylnorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin- (GeneralProcedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-465-{N′-(3-fluorophenylacetyl)-4- (3-fluorophenylacetyl)-4-5-amino-7-methyl-5,7- C-R 502.3 methylnorleucinyl}-amino-7-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General ProcedureC-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-475-{N′-(cyclopentylacetyl)-4- (cyclopentylacetyl)-4-5-amino-7-methyl-5,7- C-R 476.3 methylnorleucinyl}-amino-7-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General ProcedureC-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-485-{N′-(cyclohexylacetyl)-4- (cyclohexylacetyl)-4- 5-amino-7-methyl-5,7-C-R 490.3 methylnorleucinyl}-amino-7- methylnorleucine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-49 5-{N′-(cyclopropylacetyl)-4-(cyclopropylacetyl)-4- 5-amino-7-methyl-5,7- C-R 448.2methylnorleucinyl}-amino-7- methylnorleucine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-50 5-{N′-(2-thiopheneacetyl)-4-(2-thiopheneacetyl)-4- 5-amino-7-methyl-5,7- C-R 490.2methylnorleucinyl}-amino-7- methylnorleucine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-51 5-{N′-(isovaleryl)-4- (isovaleryl)-4-5-amino-7-methyl-5,7- C-R 450.3 methylnorleucinyl}-amino-7-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General ProcedureC-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-52 5-{N′-(3- (3-5-amino-7-methyl-5,7- C-R 552.3 (trifluoromethyl)phenylacetyl)-4-(trifluoromethyl)phenyl- dihydro-6H- methylnorleucinyl}-amino-7-acetyl)-4-methylnorleucine dibenz(bd]azepin-6-one methyl-5,7-dihydro-6H-(General Procedure C-Q) dibenz[b,d]azepin-6-one 7C-535-{N′-(4-fluorophenylacetyl)-4- (4-fluorophenylacetyl)-4-5-amino-7-methyl-5,7- C-R 502.3 methylnorleucinyl}-amino-7-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General ProcedureC-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-545-{N′-(3,4-difluorophenylacetyl)-4- (3,4-difluorophenylacetyl)-5-amino-7-methyl-5,7- C-R 520.2 methylnorleucinyl}-amino-7-4-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General ProcedureC-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-555-{N′-(2,4-difluorophenylacetyl)-4- (2,4-difluorophenylacetyl)-5-amino-7-methyl-5,7- C-R 520.3 methylnorleucinyl}-amino-7-4-methylnorleucine dihydro-6H- methyl-5,7-dihydro-6H- (General ProcedureC-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-565-{N′-(3-fluorophenylacetyl)-4- (3-fluorophenylacetyl)-4-5-amino-7-methyl-5,7- C-R 542.3 cyclohexylhomoalaninyl}-amino-7-cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (GeneralProcedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-575-{N′-(cyclopentylacetyl)-4- (cyclopentylacetyl)-4-5-amino-7-methyl-5,7- C-R 516.3 cyclohexylhomoalaninyl}-amino-7-cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (GeneralProcedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-585-{N′-(cyclohexylacetyl)-4- (cyclohexylacetyl)-4- 5-amino-7-methyl-5,7-C-R 530.4 cyclohexylhomoalaninyl}-amino-7- cyclohexylhomoalaninedihydro-6H- methyl-5,7-dihydro-6H- (General Procedure C-Q)dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-595-{N′-(cyclopropylacetyl)-4- (cyclopropylacetyl)-4-5-amino-7-methyl-5,7- C-R 488.3 cyclohexylhomoalaninyl}-amino-7-cyclohexylhomoalanine dihydro-6H- methyl-5,7-dihydro-6H- (GeneralProcedure C-Q) dibenz[bd]azepin-6-one dibenz[b,d]azepin-6-one 7C-605-{N′-(isovaleryl)-4- (isovaleryl)-4- 5-amino-7-methyl-5,7- C-R 490.3cyclohexylhomoalaninyl}-amino-7- cyclohexylhomoalanine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-61 5-{N′-(4-fluorophenylacetyl)-4-(4-fluorophenylacetyl)-4- 5-amino-7-methyl-5,7- C-R 542.3cyclohexylhomoalaninyl}-amino-7- cyclohexylhomoalanine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-62 5-{N′-(3,4-difluorophenylacetyl)-4-(3,4-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 560.3cyclohexylhomoalaninyl}-amino-7- 4-cyclohexylhomoalanine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-63 5-{N′-(2,4-difluorophenylacetyl)-4-(2,4-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 560.3cyclohexylhomoalaninyl}-amino-7- 4-cyclohexylhomoalanine dihydro-6H-methyl-5,7-dihydro-6H- (General Procedure C-Q) dibenz[bd]azepin-6-onedibenz[b,d]azepin-6-one 7C-64 5-{N′-(3-fluorophenylacetyl)-6-(3-fluorophenylacetyl)-6- 5-amino-7-methyl-5,7- C-R 506.2fluoronorleucinyl}-amino-7-methyl- fluoronorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-65 5-{N′-(cyclopentylacetyl)-6-(cyclopentylacetyl)-6- 5-amino-7-methyl-5,7- C-R 480.3fluoronorleucinyl}-amino-7-methyl- fluoronorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-66 5-{N′-(cyclohexylacetyl)-6-(cyclohexylacetyl)-6- 5-amino-7-methyl-5,7- C-R 494.3fluoronorleucinyl}-amino-7-methyl- fluoronorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-67 5-{N′-(cyclopropylacetyl)-6-(cyclopropylacetyl)-6- 5-amino-7-methyl-5,7- C-R 452.2fluoronorleucinyl}-amino-7-methyl- fluoronorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-68 5-{N′-(isovaleryl)-6- (isovaleryl)-6-5-amino-7-methyl-5,7- C-R 454.2 fluoronorleucinyl}-amino-7-methyl-fluoronorleucine dihydro-6H- 5,7-dihydro-6H-dibenz[b,d]azepin- (GeneralProcedure C-Q) dibenz[bd]azepin-6-one 6-one 7C-69 5-{N′-(3-(3-(trifluoro- 5-amino-7-methyl-5,7- C-R 556.2(trifluoromethyl)phenylacetyl)-6- methyl)phenylacetyl)- dihydro-6H-fluoronorleucinyl}-amino-7-methyl- 6-fluoronorleucinedibenz[bd]azepin-6-one 5,7-dihydro-6H-dibenz[b,d]azepin- (GeneralProcedure C-Q) 6-one 7C-70 5-{N′-(4-fluorophenylacetyl)-6-(4-fluorophenylacetyl)-6- 5-amino-7-methyl-5,7- C-R 506.2fluoronorleucinyl}-amino-7-methyl- fluoronorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-71 5-{N′-(3,4-difluorophenylacetyl)-6-(3,4-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 524.2fluoronorleucinyl}-amino-7-methyl- 6-fluoronorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-72 5-{N′-(2,4-difluorophenylacetyl)-6-(2,4-difluorophenylacetyl)- 5-amino-7-methyl-5,7- C-R 524.2fluoronorleucinyl}-amino-7-methyl- 6-fluoronorleucine dihydro-6H-5,7-dihydro-6H-dibenz[b,d]azepin- (General Procedure C-Q)dibenz[bd]azepin-6-one 6-one 7C-73 5-{N′-(4-methoxyphenylacetyl)-L-4-methoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 458.2alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-74 5-{N′-(3-(4- 3-(4-methoxy- 5-(L-alaninyl)-amino-7- C-P 472.2methoxyphenyl)propionyl)-L- phenyl)propionic methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-755-{N′-(1-naphthylacetyl)-L- 1-naphthylacetic acid5-(L-alaninyl)-amino-7- C-P 478.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-76 5-{N′-(3,4- 3,4-methylene-5-(L-alaninyl)-amino-7- C-P 472.2 methylenedioxyphenylacetyl)-L-dioxyphenylacetic methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7-acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)one 7C-77 5-{N′-(hydrocinnamyl)-L- hydrocinnamic acid5-(L-alaninyl)-amino-7- C-P 442.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-78 5-{N′-(octanoyl)-L-alaninyl}- octanoicacid 5-(L-alaninyl)-amino-7- C-P 436.2 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-79 5-{N′-(3-(3- 3-(3-hydroxy-5-(L-alaninyl)-amino-7- C-P 458.2 hydroxyphenyl)propionyl)-L-phenyl)propionic methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7-acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Lancaster)one 7C-80 5-{N′-(3-(4- 3-(4-methyl- 5-(L-alaninyl)-amino-7- C-P 456.2methylphenyl)propionyl)-L- phenyl)propionic methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Lancaster) one 7C-81 5-{N′-(3-(4-3-(4-chloro- 5-(L-alaninyl)-amino-7- C-P 476.1,chlorophenyl)propionyl)-L- phenyl)propionic methyl-5,7-dihydro-6H- 478.1alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Trans World) one 7C-825-{N′-(3-phenylbutyryl)-L- 3-phenylbutyric acid 5-(L-alaninyl)-amino-7-C-P 456.2 alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-835-{N′-(3-(4- 3-(4-hydroxy- 5-(L-alaninyl)-amino-7- C-P 458.2hydroxyphenyl)propionyl)-L- phenyl)propionic methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-845-{N′-(3,4,5-trifluorophenylacetyl)- 3,4,5-trifluorophenylacetic5-(L-alaninyl)-amino-7- C-P 482.1 L-alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Fluorochem)dibenz[b,d]azepin-6-one one 7C-85 5-{N′-(4-(4- 4-(4-methoxy-5-(L-alaninyl)-amino-7- C-P 486.2 methoxyphenyl)butyryl)-L-phenyl)butyric methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- aciddibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one7C-86 5-{N′-(3- mono-methyl succinate = 5-(L-alaninyl)-amino-7- C-P424.1 (Methoxycarbonyl)propionyl)-L- 3-(Methoxy- methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- carbonyl)propionic dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- acid one (Aldrich) 7C-875-{N′-(4-phenylbutyryl)-L- 4-phenylbutyric acid 5-(L-alaninyl)-amino-7-C-P 456.2 alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-885-{N′-(3-(benzylthio)-propionyl)-L- 3-(benzylthio)-5-(L-alaninyl)-amino-7- C-P 488.2 alaninyl}-amino-7-methyl-5,7-propionic acid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-(Sigma-Aldrich Rare) dibenz[b,d]azepin-6-one one 7C-895-{N′-(3-methylpentanoyl)-L- 3-methylpentanoic acid5-(L-alaninyl)-amino-7- C-P 408.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-90 5-{N′-(7-carbomethoxyheptanoyl)-suberic acid monomethyl 5-(L-alaninyl)-amino-7- C-P 480.2L-alaninyl}-amino-7-methyl-5,7- ester = 7- methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- carbomethoxyheptanoicdibenz[b,d]azepin-6-one one acid (Aldrich) 7C-915-{N′-(2-indanylacetyl)-L- 2-indanylacetic acid 5-(L-alaninyl)-amino-7-C-P 468.2 alaninyl}-amino-7-methyl-5,7- (Lancaster)methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-92 5-{N′-(5-Carbomethoxypentanoyl)-monomethyl adipate = 5- 5-(L-alaninyl)-amino-7- C-P 452.2L-alaninyl}-amino-7-methyl-5,7- Carbomethoxypentanoicmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- aciddibenz[b,d]azepin-6-one one (Aldrich) 7C-93 5-{N′-(2-methyl-3-2-methyl-3- 5-(L-alaninyl)-amino-7- C-P 482.2Benzofuranacetyl)-L-alaninyl}- Benzofuranacetic acidmethyl-5,7-dihydro-6H- amino-7-methyl-5,7-dihydro-6H- (Maybridge)dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-945-{N′-(propionyl)-L-alaninyl}- propionic acid 5-(L-alaninyl)-amino-7-C-P 366.1 amino-7-methyl-5,7-dihydro-6H- (Aldrich)methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one7C-95 5-{N′-(3-methoxypropionyl)-L- 3-methoxypropionic acid5-(L-alaninyl)-amino-7- C-P 396.1 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-96 5-{N′-(3-(4- 3-(4-fluoro-5-(L-alaninyl)-amino-7- C-P 460.2 fluorophenyl)propionyl)-L-phenyl)propionic methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7-acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (TransWorld) one 7C-97 5-{N′-(3-(4- 3-(4-fluoro- 5-(L-alaninyl)-amino-7- C-P476.1 fluorophenoxy)propionyl)-L- phenoxy)propionicmethyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- aciddibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Maybridge) one7C-98 5-{N′-(4-toluenesulfonylacetyl)-L- 4-toluenesulfonyl-5-(L-alaninyl)-amino-7- C-P 506.1 alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Lancaster)dibenz[b,d]azepin-6-one one 7C-99 5-{N′-(3-pentenoyl)-L-alaninyl}-3-pentenoic acid 5-(L-alaninyl)-amino-7- C-P 392.2amino-7-methyl-5,7-dihydro-6H- (Fluka) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-100 5-{N′-(4-(2,4-4-(2,4-dichloro- 5-(L-alaninyl)-amino-7- C-P 540.1,dichlorophenoxy)butyryl)-L- phenoxy)butyric methyl-5,7-dihydro-6H- 542.1alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-1015-{N′-(2,3-dichlorophenoxyacetyl)- 2,3-dichlorophenoxy-5-(L-alaninyl)-amino-7- C-P 512.1, L-alaninyl}-amino-7-methyl-5,7-acetic acid methyl-5,7-dihydro-6H- 514.1 dihydro-6H-dibenz[b,d]azepin-6-(Aldrich) dibenz[b,d]azepin-6-one one 7C-102 5-{N′-(3-(4- 3-(4-chloro5-(L-alaninyl)-amino-7- C-P 504.1, chlorobenzoyl)propionyl)-L-benzoyl)propionic methyl-5,7-dihydro-6H- 506.1alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-1035-{N′-(4′-fluorosuccinanilyl)-L- 4′-fluorosuccinanilic acid5-(L-alaninyl)-amino-7- C-P 503.2 alaninyl}-amino-7-methyl-5,7-(Sigma-Aldrich Rare) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1045-{N′-(n- n-(diphenyl- 5-(L-alaninyl)-amino-7- C-P 589.3(diphenylmethyl)glutaramyl)-L- methyl)glutaramic methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Sigma-Aldrich Rare) one 7C-1055-{N′-(2-fluorophenylacetyl)-L- 2-fluorophenylacetic acid5-(L-alaninyl)-amino-7- C-P 446.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-106 5-{N′-(cyanoacetyl)-L-alaninyl}-cyanoacetic acid 5-(L-alaninyl)-amino-7- C-P 377.1amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-1075-{N′-(succinanilyl)-L-alaninyl}- succinanilic acid5-(L-alaninyl)-amino-7- C-P 485.2 amino-7-methyl-5,7-dihydro-6H-(Sigma-Aldrich Rare) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-108 5-{N′-(2,4-dichlorophenoxyaceyl)-2,4-dichlorophenoxy- 5-(L-alaninyl)-amino-7- C-P 512.1,L-alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H- 514.1dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-109 5-{N′-(2-nitrophenylacetyl)-L- 2-nitrophenylacetic acid5-(L-alaninyl)-amino-7- C-P 473.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-110 5-{N′-(beta-propylhydrocinnamyl)-beta-propylhydrocinnamic 5-(L-alaninyl)-amino-7- C-P 484.3L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Sigma-Aldrich Rare)dibenz[b,d]azepin-6-one one 7C-111 5-{N′-(3-(2,4- 3-(2,4-dimethyl-5-(L-alaninyl)-amino-7- C-P 498.2 dimethylbenzoyl)propionyl)-L-benzoyl)propionic methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7-acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6-(Sigma-Aldrich Rare) one 7C-112 5-{N′-(2-fluoro-3- 2-fluoro-3-5-(L-alaninyl)-amino-7- C-P 514.3 (trifluoromethyl)phenylacetyl)-L-(trifluoromethyl)phenyl- methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acetic acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Fluorochem) one 7C-1135-{N′-(2,4,6-trifluorophenylacetyl)- 2,4,6-trifluorophenyl-5-(L-alaninyl)-amino-7- C-P 482.2 L-alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Fluorochem)dibenz[b,d]azepin-6-one one 7C-114 5-{N′-(4-fluoro-2- 4-fluoro-2-5-(L-alaninyl)-amino-7- C-P 514.2 (trifluoromethyl)phenylacetyl)-L-(trifluoromethyl)phenyl- methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acetic acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Fluorochem) one 7C-1155-{N′-(2-fluoro-4- 2-fluoro-4- 5-(L-alaninyl)-amino-7- C-P 514.2(trifluoromethyl)phenylacetyl)-L- (trifluoromethyl)phenyl-methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- acetic aciddibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Fluorochem) one7C-116 5-{N′-(4-hydroxyphenylacetyl)-L- 4-hydroxyphenylacetic5-(L-alaninyl)-amino-7- C-P 444.2 alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)dibenz[b,d]azepin-6-one one 7C-117 5-{N′-(4-methoxyphenoxyacetyl)-4-methoxyphenoxyacetic 5-(L-alaninyl)-amino-7- C-P 474.2L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) dibenz[b,d]azepin-6-one one7C-118 5-{N′-(2-methoxyphenylacetyl)-L- 2-methoxyphenylacetic5-(L-alaninyl)-amino-7- C-P 458.2 alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)dibenz[b,d]azepin-6-one one 7C-119 5-{N-(2-bromophenylacetyl)-L-2-bromophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 508.1alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1205-{N′-(4-benzyloxyphenoxyacetyl)- 4-benzyloxyphenoxy-5-(L-alaninyl)-amino-7- C-P 550.2 L-alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Lancaster)dibenz[b,d]azepin-6-one one 7C-121 5-{N′-(4-hydroxyphenoxyacetyl)-L-4-hydroxyphenoxy- 5-(L-alaninyl)-amino-7- C-P 460.2alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Acros) dibenz[b,d]azepin-6-one one7C-122 5-{N′-(levulinyl)-L-alaninyl}- levulinic acid5-(L-alaninyl)-amino-7- C-P 408.2 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-123 5-{N′-(2-hydroxyphenylacetyl)-L-2-hydroxyphenyl- 5-(L-alaninyl)-amino-7- C-P 444.2alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-124 5-{N′-(3,4- 3,4-dimethoxyphenyl- 5-(L-alaninyl)-amino-7- C-P488.2 dimethoxyphenylacetyl)-L- acetic acid methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- (Aldrich) dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- one 7C-125 5-{N′-(3-(4- 3-(4-methoxy-5-(L-alaninyl)-amino-7- C-P 500.2 methoxybenzoyl)propionyl)-L-benzoyl)propionic methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7-acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)one 7C-126 5-{N′-(3-(4- fenbufen = 3-(4- 5-(L-alaninyl)-amino-7- C-P546.2 Phenylbenzoyl)propionyl)-L- Phenylbenzoyl)propionicmethyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- aciddibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Sigma-AldrichRare) one 7C-127 5-{N′-(3-hydroxyphenylacetyl)-L- 3-hydroxyphenyl-5-(L-alaninyl)-amino-7- C-P 444.2 alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)dibenz[b,d]azepin-6-one one 7C-128 5-{N′-(N-acetyl-N-phenylglycinyl)-N-acetyl-N-phenylglycine 5-(L-alaninyl)-amino-7- C-P 485.2L-alaninyl}-amino-7-methyl-5,7- (Kodak) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1295-{N′-(thiophene-3-acetyl)-L- thiophene-3-acetic acid5-(L-alaninyl)-amino-7- C-P 434.1 alaninyl}-amino-7-methyl-5,7- (Acros)methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-130 5-{N′-(6-phenylhexanoyl)-L-6-phenylhexanoic acid 5-(L-alaninyl)-amino-7- C-P 484.3alaninyl}-amino-7-methyl-5,7- (Avocado) methyl-5,7-dihydro-6H-dihydro-6h-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1315-{N′-(cyclohexanebutyryl)-L- cyclohexanebutyric acid5-(L-alaninyl)-amino-7- C-P 462.3 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-132 5-{N′-(2,3,5-trifluorophenylacetyl)-2,3,5-trifluorophenyl- 5-(L-alaninyl)-amino-7- C-P 482.2L-alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Fluorochem) dibenz[b,d]azepin-6-one one7C-133 5-{N′-(2,4,5-trifluorophenylacetyl)- 2,4,5-trifluorophenyl-5-(L-alaninyl)-amino-7- C-P 482.2 L-alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Fluorochem)dibenz[b,d]azepin-6-one one 7C-134 5-{N′-(vinylacetyl)-L-alaninyl}-vinylacetic acid 5-(L-alaninyl)-amino-7- C-P 378.2amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-1355-{N′-(3-methylthiopropionyl)-L- 3-methylthiopropionic acid5-(L-alaninyl)-amino-7- C-P 412.1 alaninyl}-amino-7-methyl-5,7-(Lancaster) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-136 5-{N′-(3-nitrophenylacetyl)-L-3-nitrophenylacetic acid 5-(L-alaninyl)-amino-7- C-P 473.2alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1375-{N′-(n-tert-butylsuccinamyl)-L- n-tert-butylsuccinamic acid5-(L-alaninyl)-amino-7- C-P 465.2 alaninyl}-amino-7-methyl-5,7-(Sigma-Aldrich Rare) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1385-{N′-(4-bromophenylacetyl)-L- 4-bromophenylacetic acid5-(L-alaninyl)-amino-7- C-P 506.1, alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- 508.1 dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-139 5-{N′-(3-(4- 3-(4-fluoro-5-(L-alaninyl)-amino-7- C-P 488.2 fluorobenzoyl)propionyl)-L-benzoyl)propionic methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7-acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)one 7C-140 5-{N′-(o-chlorophenoxyacetyl)-L- o-chlorophenoxyacetic5-(L-alaninyl)-amino-7- C-P 478.1, alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- 480.1 dihydro-6H-dibenz[b,d]azepin-6- (Lancaster)dibenz[b,d]azepin-6-one one 7C-141 5-{N′-(p-tolylaceyl)-L-alaninyl}-p-tolylacetic acid 5-(L-alaninyl}-amino-7- C-P 442.2amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-1425-{N′-(m-tolylacetyl)-L-alaninyl}- m-tolylacetic acid5-(L-alaninyl)-amino-7- C-P 442.2 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-143 5-{N′-(3,4-dichlorophenylacetyl)-3,4-dichlorophenyl- 5-(L-alaninyl)-amino-7- C-P 496.1,L-alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H- 498.1dihydro-6H-dibenz[b,d]azepin-6- (Fairfield) dibenz[b,d]azepin-6-one one7C-144 5-{N′-(4-chlorophenoxyacetyl)-L- 4-chlorophenoxy-5-(L-alaninyl)-amino-7- C-P 478.1, alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- 480.2 dihydro-6H-dibenz[b,d]azepin-6- (GrandIsland Biological) dibenz[b,d]azepin-6-one one 7C-1455-{N′-(3-methylphenoxyacetyl)-L- 3-methylphenoxy-5-(L-alaninyl)-amino-7- C-P 458.2 alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Lancaster)dibenz[b,d]azepin-6-one one 7C-146 5-{N′-(4-isopropylphenoxyacetyl)-4-isopropylphenoxy- 5-(L-alaninyl)-amino-7- C-P 486.2L-alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) dibenz[b,d]azepin-6-one one7C-147 5-{N′-(4-phenoxyphenylacetyl)-L- 4-phenoxyphenyl-5-(L-alaninyl)-amino-7- C-P 520.2 alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (TransWorld) dibenz[b,d]azepin-6-one one 7C-1485-{N′-(phenylmercaptoacetyl)-L- phenylmercaptoacetic acid5-(L-alaninyl)-amino-7- C-P 460.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-149 5-{N′-(4-ethoxyphenylacetyl)-L-4-ethoxyphenylacetic acid 5-(L-alaninyl)-amino-7- C-P 472.2alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1505-{N′-(2,5- 2,5-dimethoxyphenyl- 5-(L-alaninyl)-amino-7- C-P 488.2dimethoxyphenylacetyl)-L- acetic acid methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- (Aldrich) dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- one 7C-1515-{N′-(o-tolylacetyl)-L-alaninyl}- o-tolylacetic acid5-(L-alaninyl)-amino-7- C-P 442.2 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-152 5-{N′-(3,3-diphenylpropionyl)-L-3,3-diphenylpropionic acid 5-(L-alaninyl)-amino-7- C-P 518.2alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1535-{N′-(3-phenoxypropionyl)-L- 3-phenoxypropionic acid5-(L-alaninyl)-amino-7- C-P 458.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-154 5-{N′-(4- 4-(trifluoro-5-(L-alaninyl)-amino-7- C-P 496.2 (trifluoromethyl)phenylacetyl)-L-methyl)phenylacetic methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7-acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Maybridge)one 7C-155 5-{N′-((4-methylphenoxy)acetyl)- (4-methylphenoxy)acetic5-(L-alaninyl)-amino-7- C-P 458.2 L-alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)dibenz[b,d]azepin-6-one one 7C-156 5-{N′-(2-phenoxyphenylacetyl)-L-2-phenoxyphenylacetic 5-(L-alaninyl)-amino-7- C-P 520.2alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Trans World) dibenz[b,d]azepin-6-oneone 7C-157 5-{N′-(3-phenoxyphenylacetyl)-L- 3-phenoxyphenylacetic5-(L-alaninyl)-amino-7- C-P 520.2 alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)dibenz[b,d]azepin-6-one one 7C-158 5-{N′-(3,4-dichlorophenoxyacetyl)-3,4-dichlorophenoxy- 5-(L-alaninyl)-amino-7- C-P 512.1,L-alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H- 514.1dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-159 5-{N′-(4-fluorophenoxyacetyl)-L- 4-fluorophenoxyacetic acid5-(L-alaninyl)-amino-7- C-P 462.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-160 5-{N′-(3,4,5- 3,4,5-trimethoxy-5-(L-alaninyl)-amino-7- C-P 518.2 trimethoxyphenylacetyl)-L-phenylacetic methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7- aciddibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one7C-161 5-{N′-(2,4-dichlorophenylacetyl)- 2,4-dichlorophenyl-5-(L-alaninyl)-amino-7- C-P 496.1, L-alaninyl}-amino-7-methyl-5,7-acetic acid methyl-5,7-dihydro-6H- 498.1 dihydro-6H-dibenz[b,d]azepin-6-(Fairfield) dibenz[b,d]azepin-6-one one 7C-1625-{N′-(4-thianaphthenacetyl)-L- 4-thianaphthenacetic acid5-(L-alaninyl)-amino-7- C-P 484.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-163 5-{N′-(methoxyacetyl)-L-alaninyl}-methoxyacetic acid 5-(L-alaninyl)-amino-7- C-P 382.2amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-1645-{N′-(ethoxyacetyl)-L-alaninyl}- ethoxyacetic acid5-(L-alaninyl)-amino-7- C-P 396.2 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-165 5-{N′-(phenoxyacetyl)-L-alaninyl}-phenoxyacetic acid 5-(L-alaninyl)-amino-7- C-P 444.2amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-1665-{N′-(3-methoxyphenoxyacetyl)- 3-methoxyphenoxy-5-(L-alaninyl)-amino-7- C-P 474.2 L-alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)dibenz[b,d]azepin-6-one one 7C-167 5-{N′-(4-butoxyphenylacetyl)-L-4-butoxyphenyl- 5-(L-alaninyl)-amino-7- C-P 500.3alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) dibenz[b,d]azepin-6-one one7C-168 5-{N′-(3-(2- 3-(2-methoxy- 5-(L-alaninyl)-amino-7- C-P 472.2methoxyphenyl)propionyl)-L- phenyl)propionic methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-1695-{N′-(N,N-dimethylsuccinamyl)- N,N-dimethylsuccinamic5-(L-alaninyl)-amino-7- C-P 437.2 L-alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Lancaster)dibenz[b,d]azepin-6-one one 7C-170 5-{N′-(3-(3,4- 3-(3,4-methylene-5-(L-alaninyl)-amino-7- C-P 486.2 methylenedioxyphenyl)propionyl)-dioxyphenyl)pro- methyl-5,7-dihydro-6H- L-alaninyl}-amino-7-methyl-5,7-pionic acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6-(Lilly) one 7C-171 5-{N′-(2-Chloro-6- 2-Chloro-6-5-(L-alaninyl)-amino-7- C-P 480.1, fluorophenylacetyl)-L-alaninyl}-fluorophenylacetic acid methyl-5,7-dihydro-6H- 482.1amino-7-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-172 5-{N′-(2,5-difluorophenylacetyl)-L-2,5-difluorophenyl- 5-(L-alaninyl)-amino-7- C-P 464.2alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-173 5-{N′-(pentafluorophenoxyacetyl)- pentafluorophenoxy-5-(L-alaninyl)-amino-7- C-P 534.2 L-alaninyl}-amino-7-methyl-5,7- aceticacid methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)dibenz[b,d]azepin-6-one one 7C-174 5-{N′-(3,5- 3,5-bis(tri-5-(L-alaninyl)-amino-7- C-P 564.2 bis(trifluoromethyl)phenylacetyl)-fluoromethyl)phenyl- methyl-5,7-dihydro-6H-L-alaninyl}-amino-7-methyl-5,7- acetic acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Aldrich) one 7C-175 5-{N′-(3,5-3,5-dimethylphenoxy- 5-(L-alaninyl)-amino-7- C-P 472.2dimethylphenoxyacetyl)-L- acetic acid methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- (Sigma-Aldrich Rare)dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- one 7C-1765-{N′-(4-chlorophenylacetyl)-L- 4-chlorophenylacetic acid5-(L-alaninyl)-amino-7- C-P 462.1, alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- 464.1 dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-177 5-{N′-(3-chlorophenoxyacetyl)-L-3-chlorophenoxy- 5-(L-alaninyl)-amino-7- C-P 478.1,alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H- 480.2dihydro-6H-dibenz[b,d]azepin-6- (Lancaster) dibenz[b,d]azepin-6-one one7C-178 5-{N′-(benzo [b] thiophene-3- benzo [b] thiophene-3-5-(L-alaninyl)-amino-7- C-P 484.2 acetyl)-L-alaninyl}-amino-7- aceticacid methyl-5,7-dihydro-6H- methyl-5,7-dihydro-6H- (Lancaster)dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-179 5-{N′-(3,5-3,5-dimethoxyphenyl- 5-(L-alaninyl)-amino-7- C-P 488.2dimethoxyphenylacetyl)-L- acetic acid methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- (Aldrich) dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- one 7C-1805-{N′-(2,5-dimethylphenylacetyl)- 2,5-dimethylphenylacetic5-(L-alaninyl)-amino-7- C-P 456.2 L-alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Lancaster)dibenz[b,d]azepin-6-one one 7C-181 5-{N′-(mesitylacetyl)-L-alaninyl}-mesitylacetic acid 5-(L-alaninyl)-amino-7- C-P 470.2amino-7-methyl-5,7-dihydro-6H- (Lancaster) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-1825-{N′-(4-biphenylacetyl)-L- 4-biphenylacetic acid5-(L-alaninyl)-amino-7- C-P 504.2 alaninyl}-amino-7-methyl-5,7-(Lancaster) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-183 5-{N′-(N-(tert-butoxycarbonyl)-3-boc-beta-ala-oh = N-(tert- 5-(L-alaninyl)-amino-7- C-P 381.2,aminopropionyl)-L-alaninyl}- butoxycarbonyl)-3- methyl-5,7-dihydro-6H-481.2 amino-7-methyl-5,7-dihydro-6H- aminopropionic aciddibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one (Sigma) 7C-1845-{N′-(trans-styrylacetyl)-L- trans-styrylacetic acid5-(L-alaninyl)-amino-7- C-P 454.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-185 5-{N′-(4-acetamidobutyryl)-L-4-acetamidobutyric acid 5-(L-alaninyl)-amino-7- C-P 437.2alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1865-{N′-(3-(2- 3-(2-chloro- 5-(L-alaninyl)-amino-7- C-P 476.2,chlorophenyl)propionyl)-L- phenyl)propionic methyl-5,7-dihydro-6H- 478.2alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Trans World) one 7C-1875-{N′-(butyryl)-L-alaninyl}-amino- butyric acid 5-(L-alaninyl)-amino-7-C-P 380.2 7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-1885-{N′-(trans-3-hexenoyl)-L- trans-3-hexenoic acid5-(L-alaninyl)-amino-7- C-P 406.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-189 5-{N′-(5-phenylvaleryl)-L-5-phenylvaleric acid 5-(L-alaninyl)-amino-7- C-P 470.2alaninyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-1905-{N′-(3-(3- 3-(3-methoxy- 5-(L-alaninyl)-amino-7- C-P 472.2methoxyphenyl)propionyl)-L- phenyl)propionic methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Lancaster) one 7C-1915-{N′-(4-chloro-beta- 4-chloro-beta- 5-(L-alaninyl)-amino-7- C-P 490.2,methylhydrocinnamyl)-L-alaninyl}- methylhydrocinnamic acidmethyl-5,7-dihydro-6H- 492.2 amino-7-methyl-5,7-dihydro-6H-(Sigma-Aldrich Rare) dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one7C-192 5-{N′-(3-(trifluoromethyl)butyryl)- 3-(trifluoro-5-(L-alaninyl)-amino-7- C-P 448.2 L-alaninyl}-amino-7-methyl-5,7-methyl)butyric acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Fluorochem) dibenz[b,d]azepin-6-one one7C-193 5-{N′-(methanesulfonylacetyl)-L- methanesulfonylacetic acid5-(L-alaninyl)-amino-7- C-P 430.1 alaninyl}-amino-7-methyl-5,7-(Lancaster) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-194 5-{N′-(alpha-naphthoxyacetyl)-L-alpha-naphthoxy- 5-(L-alaninyl)-amino-7- C-P 494.2alaninyl}-amino-7-methyl-5,7- acetic acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-195 5-{N′-(3-(4- 3-(4-phenoxy- 5-(L-alaninyl)-amino-7- C-P 562.2phenoxybenzoyl)propionyl)-L- benzoyl)propionic methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Sigma-Aldrich Rare) one 7C-1965-{N′-(3-(2- 3-(2-trifluoro- 5-(L-alaninyl)-amino-7- C-P 538.2trifluoromethylbenzoyl)propionyl)- methylbenzoyl)pro-methyl-5,7-dihydro-6H- L-alaninyl}-amino-7-methyl-5,7- pionic aciddibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Sigma-AldrichRare) one 7C-197 5-{N′-(3-benzoylamino-3-phenyl-3-benzoylamino-3-phenyl- 5-(L-alaninyl)-amino-7- C-P 561.2propionyl)-L-alaninyl}-amino-7- propionic acid methyl-5,7-dihydro-6H-methyl-5,7-dihydro-6H- (Sigma-Aldrich Rare) dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-198 5-{N′-(4- levulinic acid oxime = 4-5-(L-alaninyl)-amino-7- C-P 423.2 (hydroxyimino)pentanoyl)-L-(hydroxyimino)pentanoic methyl-5,7-dihydro-6H-alaninyl}-amino-7-methyl-5,7- acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Sigma-Aldrich Rare) one 7C-1995-{N′-(4′-methylglutaranilyl)-L- 4′-methylglutaranilic acid5-(L-alaninyl)-amino-7- C-P 499.2 alaninyl}-amino-7-methyl-5,7-(Sigma-Aldrich Rare) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-2005-{N′-((4-(4-ethyl-phenoxy)- (4-(4-ethyl-phenoxy)-5-(L-alaninyl)-amino-7- C-P 564.2 phenoxy)-acetyl)-L-alaninyl}-phenoxy)-acetic acid methyl-5,7-dihydro-6H-amino-7-methyl-5,7-dihydro-6H- (Sigma-Aldrich Rare)dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-2015-{N′-(3-Benzoyl-3- 3-Benzoyl-3- 5-(L-alaninyl)-amino-7- C-P 528.2,phenylpropionyl)-L-alaninyl}- phenylpropionic acidmethyl-5,7-dihydro-6H- 546.2 amino-7-methyl-5,7-dihydro-6H-(Sigma-Aldrich Rare) dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one7C-202 5-{N′-(4- 4-(hydroxy- 5-(L-alaninyl)-amino-7- C-P 456.2,(hydroxymethyl)phenoxyacetyl)-L- methyl)phenoxy- methyl-5,7-dihydro-6H-474.2 alaninyl}-amino-7-methyl-5,7- acetic acid dibenz[b,d]azepin-6-onedihydro-6H-dibenz[b,d]azepin-6- (Sigma) one 7C-2035-{N′-(4,4,4-trifluorobutyryl)-L- 4,4,4-trifluorobutyric acid5-(L-alaninyl)-amino-7- C-P 434.1 alaninyl}-amino-7-methyl-5,7-(Fluorochem) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-204 5-{N′-(3-isobutyrylamino-3-phenyl-3-isobutyrylamino-3- 5-(L-alaninyl)-amino-7- C-P 527.3propionyl)-L-alaninyl}-amino-7- phenyl-propionic acidmethyl-5,7-dihydro-6H- methyl-5,7-dihydro-6H- (Sigma-Aldrich Rare)dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-2055-{N′-((2-methylphenoxy)acetyl)- (2-methylphenoxy)acetic5-(L-alaninyl)-amino-7- C-P 458.2 L-alaninyl}-amino-7-methyl-5,7- acidmethyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6- (Lancaster)dibenz[b,d]azepin-6-one one 7C-206 5-{N′-(3- 3-(phenyl-5-(L-alaninyl)-amino-7- C-P 506.2 (phenylsulfonyl)propionyl)-L-sulfonyl)propionic methyl-5,7-dihydro-6H- alaninyl}-amino-7-methyl-5,7-acid dibenz[b,d]azepin-6-one dihydro-6H-dibenz[b,d]azepin-6- (Aldrich)one 7C-207 5-{N′-(4-nitrophenylacetyl)-L- 4-nitrophenylacetic acid5-(L-alaninyl)-amino-7- C-P 473.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-208 5-{N′-(3-ethoxypropionyl)-L-3-ethoxypropionic acid 5-(L-alaninyl)-amino-7- C-P 410.2alaninyl}-amino-7-methyl-5,7- (TCI) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-2095-{N′-(2,3-difluoromandelyl)-L- 2,3-difluoromandelic acid5-(L-alaninyl)-amino-7- C-P 480.2 alaninyl}-amino-7-methyl-5,7-(Fluorochem) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-210 5-{N′-(2,6-difluoromandelyl)-L-2,6-difluoromandelic acid 5-(L-alaninyl)-amino-7- C-P 480.2alaninyl}-amino-7-methyl-5,7- (Fluorochem) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-2115-{N′-(4-fluoromandelyl)-L- 4-fluoromandelic acid5-(L-alaninyl)-amino-7- C-P 462.2 alaninyl}-amino-7-methyl-5,7-(Lancaster) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-212 5-{N′-(2,5-difluoromandelyl)-L-2,5-difluoromandelic acid 5-(L-alaninyl)-amino-7- C-P 480.2alaninyl}-amino-7-methyl-5,7- (Fluorochem) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-2135-{N′-(dl-beta-phenyllactyl)-L- dl-beta-phenyllactic acid5-(L-alaninyl)-amino-7- C-P 458.2 alaninyl}-amino-7-methyl-5,7- (Sigma)methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-214 5-{N′-(dl-mandelyl}-amino-7-dl-mandelic acid or dl- 5-(L-alaninyl)-amino-7- C-P 444.2methyl-5,7-dihydro-6H- alpha-hydroxyphenylacetic methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one acid dibenz[b,d]azepin-6-one (Aldrich) 7C-2155-{N′-(p-chloromandelyl)-L- p-chloromandelic acid5-(L-alaninyl)-amino-7- C-P 444.2, alaninyl}-amino-7-methyl-5,7- (Acros)methyl-5,7-dihydro-6H- 478.1 dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-216 5-{N′-(l-alpha-hydroxyisocaproyl)-l-alpha-hydroxyisocaproic 5-(L-alaninyl)-amino-7- C-P 424.2L-alaninyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-217 5-{N′-(4-bromomandelyl)-L- 4-bromomandelic acid5-(L-alaninyl)-amino-7- C-P 522.1, alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- 524.1 dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-218 5-{N′-(l-(+)-lactyl)-L-alaninyl}-l-(+)-lactic acid 5-(L-alaninyl)-amino-7- C-P 382.2,amino-7-methyl-5,7-dihydro-6H- (Sigma) methyl-5,7-dihydro-6H- 454.2dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-2195-{N′-(d-3-phenylacetyl)-L- d-3-phenylacetic acid5-(L-alaninyl)-amino-7- C-P 458.2 alaninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-220 5-{N′-(5-methylhexanoyl)-L-5-methylhexanoic acid 5-(L-alaninyl)-amino-7- C-P 422.2alaninyl}-amino-7-methyl-5,7- (P&B) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one

General Procedure C-S

[2928] Step A: Each amino acid (150 umol) was weight into an 8- mLcapacity vial and dissolved in 1.5 mL of 10% DMF in dichloromethane(DCM). To each vial was added 0.8 mL (175 umol) of a solution of5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride(418 mg, 1.75 mmol)(from Example 7-A) and 670 mg (1.75 mmol) of PP-HOBT(from Example C-AF) dissolved in 7.5 mL DMF. This was followed by theaddition to each vial of 2 mL (approximately 200 umol) of a solution ofEDC hydrochloride in DCM (383 mg, 2.0 mmol in 20 mL DCM). After rockingthe vials at room temperature for 14 hours, approximately 100-125mg ofpolystyrene-piperidine resin (approximately 3.6 mmol/g, 350 umol, 233eq.) was added to each vial and rocking continued for 15 minutes.Methanol (2.5 mL) was added to each vial and the material put on a 1 gSCX column (Varian) pre-equilibrated with 5 mL of MeOH and 5 mL of 10%MeOH/chloroform. After pushing the liquid through the column withnitrogen, the column was washed with 5 mL of 10% MeOH/chloroform. Thecombined eluents (collected in 25 mL roundbottom flasks) were evaporatedat reduced pressure with a warm water bath at 30-35° C. and then furtherevaporated in a vacuum oven at 40-45° C. When the net weight of theresidues was below 100 mg, 5 mL of dioxane and, if necessary, 1 mL ofMeOH was added ton redissolve the residue and solvent was again removedon the rotary evaporator and in the vacuum oven. After drying in thevacuum oven overnight, an HPLC was taken of each product. HPLC showprimarily the desired product and with about 15% deblocked product(i.e., product with the BOC group removed).

[2929] Step B: To each round bottom flask was added 5 mL of 4 N HCl indioxane. After sitting at room temperature for 2-3 hours, an HPLC wastaken and was solvent removed on the rotary evaporator (bath temp 30-35°C.) and in the vacuum oven overnight (at approximately 40° C.). The HPLCof the t-butyl threonine adduct showed incomplete removal of the t-butylgroup. An additional 5 mL of 4 N HCl in dioxane was added and thereaction (at room temperature) monitored by HPLC at 4 hours andapproximately 20 hours. Complete removal of the t-butyl group wasobserved after 20 hours. All products were pure by HPLC with only asingle peak or resolved diastereomeric peaks observed except for sometrace impurities in the methione case. Yields varied from 80 to 100%.Each round bottom contained approximately 150 umoles of the amino acidlinked to 5-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one.

[2930] Step C: A stock solution of 567 mg (1.48 mmol) PP-HOBT in 8.5 mLDMF (approximately 0.175 M PP-HOBT in DMF) was prepared and 0.81 g (0.86mL, 150 umol) of this PP-HOBT solution was added to each of the nineround-bottom vessels containing the products from Step B. Clearsolutions were obtained for all, except where the linked amino acid wasalpha amino isobutyric acid. In this case, an additional 0.86 mL of DMFwas added but still the mixture remained heterogeneous. The contents ofeach of the nine round bottoms “n” (where n=1 to 9) were divided intofour equal portions (approximately 37 umols each) and placed in vials.Stock solutions (0.1 M) of the carboxylic acids were then made up in 10%DMF/DCM. The appropriate stock solution (0.3 mL, 30 umol) was then addedto each of the vials. A 0.1 M stock solution (20 mL) of EDChydrochloride in DMF was prepared. This stock solution (0.4 mL, 40 umol)was then added to each of the vials which were then capped and put on arotator for 12 hours. Normal SCX workup and evaporation of solventafforded products as white solids or clear to light caramel resins. Eachof these products was taken up in methanol/chloroform and divided intothree tared vials, plus a vial for MS and HPLC characterization. Afterevaporation of solvent, the final weights in each vial were determined.Product identity was verified by ionspray mass spec and purity assessedby reverse phase HPLC.

Example C-AF Preparation of PP-HOBT

[2931] To a stirred solution of 7.68 g (30 mmol) sulfonyl chloride in120 mL of dichloromethane was added dropwise, over a 10 min period, 5.04g (30 mmol) of 4-piperidino-piperidine (Aldrich, 90%) and 3.6 g (36mmol) of triethylamine in 30 mL of dichloromethane. A mildly exothermicreaction ensued. After stirring 2 hours at room temperature, the orangesolution was diluted with 100 mL of dichloromethane and washed with 10%sodium bicarbonate solution (2×100 mL) and brine (1×100 mL). Afterdrying over sodium sulfate, the solvent was removed at reduced pressureto afford 10.7 g of crude product as a light tan solid (R_(f)=0.5,Silica, 10% MeOH/chloroform).

[2932] To this crude material was added 200 mL of 95% EtOH/5% MeOHfollowed by 60 mL of hydrazine hydrate. The mixture was refluxed for 3hours. During the first 0.5 hour, the initially orange solution turneddeep red-orange before turning orange again. After refluxing for 3hours, most of the solvent, water and hydrazine was removed at reducedpressure. To the residue was added 50 mL of EtOH and solvent removed atreduced pressure. This was repeated 2 or more times to give a tan solidwhich was further dried in the vacuum oven to a constant weight of 13.5g. To the flask containing this solid was added 250 mL of water. Almostall of the solid went into solution, then a fine light yellowprecipitate formed. After stirring cooled in an ice bath for two hours,the solid was collected by vacuum filtration through a sintered glassfilter, and rinsed with about 20 mL of cold water. Drying in the vacuumoven at 40° C overnight afforded 7.3 g (63% yield) of the title compound(PP-HOBT) as an off-white crunchy powder, mp 195-200° C. (dec).

[2933] Using the procedures indicated, the compounds shown in Table C-5were prepared. Starting material 2 used in these procedures was preparedas described in General Procedure C-S. TABLE C-5 Example General No.Compound Starting Material 1 Starting Material 2 Procedure MS 7C-2215-{N′-(3,5-difluorophenylacetyl)- 3,5-difluorophenylacetic5-(L-methioninyl)-amino-7- C-S 524.3 L-methioninyl}-amino-7-methyl- acidmethyl-5,7-dihydro-6H- 5,7-dihydro-6H- (Aldrich) dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-222 5-{N′-(3,5-difluorophenylacetyl)-3,5-difluorophenylacetic 5-(L-2-phenylglycinyl)- C-S 526.5L-2-phenylglycinyl}-amino-7- acid amino-7-methyl-5,7-methyl-5,7-dihydro-6H- (Aldrich) dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-223 5-{N′-(3,5-difluorophenylacetyl)-3,5-difluorophenylacetic 5-(L-leucinyl)-amino-7- C-S 506.3L-leucinyl}-amino-7-methyl-5,7- acid methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- (Aldrich) dibenz[b,d]azepin-6-one one7C-224 5-{N′-(3,5-difluorophenylacetyl)- 3,5-difluorophenylacetic5-(L-2-cyclohexylglycinyl)- C-S 532.3 L-2-cyclohexylglycinyl}-amino-7-acid amino-7-methyl-5,7- methyl-5,7-dihydro-6H- (Aldrich) dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-2255-{N′-(3,5-difluorophenylacetyl)- 3,5-difluorophenylacetic5-(L-threoninyl)-amino-7- C-S 494.5 L-threoninyl}-amino-7-methyl- acidmethyl-5,7-dihydro-6H- 5,7-dihydro-6H- (Aldrich) dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-226 5-{N′-(3,5-difluorophenylacetyl)-3,5-difluorophenylacetic 5-(L-alpha-(2- C-S 532.2L-alpha-(2-thienyl)glycinyl}- acid thienyl)glycinyl)-amino-7-amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-2275-{N′-(2-thiopheneacetyl)-L- 2-thiopheneacetic acid5-(L-methioninyl)-amino-7- C-S 494.3 methioninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-228 5-{N′-(2-thiopheneacetyl)-L-2-2-thiopheneacetic acid 5-(L-2-phenylglycinyl)- C-S 496.2phenylglycinyl}-amino-7-methyl- (Aldrich) amino-7-methyl-5,7-5,7-dihydro-6H- dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-229 5-{N′-(2-thiopheneacetyl)-L-2-thiopheneacetic acid 5-(L-leucinyl)-amino-7- C-S 476.2leucinyl}-amino-7-methyl-5,7- (Aldrich) methyl-5,7-dihydro-6H-dihydro-6H-dibenz[b,d]azepin-6- dibenz[b,d]azepin-6-one one 7C-2305-{N′-(2-thiopheneacetyl)-L-2- 2-thiopheneacetic acid5-(L-2-cyclohexylglycinyl)- C-S 502.2 cyclohexylglycinyl}-amino-7-(Aldrich) amino-7-methyl-5,7- methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-2315-{N′-(2-thiopheneacetyl)-L- 2-thiopheneacetic acid5-(L-threoninyl)-amino-7- C-S 464.3 threoninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-232 5-{N′-(2-thiopheneacetyl)-L-2-thiopheneacetic acid 5-(L-alpha-(2- C-S 502.1alpha-(2-thienyl)glycinyl}-amino- (Aldrich) thienyl)glycinyl)-amino-7-7-methyl-5,7-dihydro-6H- methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-233 5-{N′-(isovaleryl)-L- isovaleric acid5-(L-methioninyl)-amino-7- C-S 454.2 methioninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-234 5-{N′-(isovaleryl)-L-2- isovalericacid 5-(L-2-phenylglycinyl)- C-S 456.4 phenylglycinyl}-amino-7-methyl-(Aldrich) amino-7-methyl-5,7- 5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-2355-{N′-(isovaleryl)-L-leucinyl}- isovaleric acid 5-(L-leucinyl)-amino-7-C-S 436.4 amino-7-methyl-5,7-dihydro-6H- (Aldrich)methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one7C-236 5-{N′-(isovaleryl)-L-2- isovaleric acid5-(L-2-cyclohexylglycinyl)- C-S 462.6 cyclohexylglycinyl}-amino-7-(Aldrich) amino-7-methyl-5,7- methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-2375-{N′-(isovaleryl)-L-threoninyl}- isovaleric acid5-(L-threoninyl)-amino-7- C-S 424.3 amino-7-methyl-5,7-dihydro-6H-(Aldrich) methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-238 5-{N′-(isovaleryl)-L-alpha-(2- isovalericacid 5-(L-alpha-(2- C-S 462.3 thienyl)glycinyl}-amino-7-methyl-(Aldrich) thienyl)glycinyl)-amino-7- 5,7-dihydro-6H-methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one7C-239 5-{N′-(phenylacetyl)-L- phenylacetic acid5-(L-methioninyl)-amino-7- C-S 488.5 methioninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-240 5-{N′-(phenylacetyl)-L-2-phenylacetic acid 5-(L-2-phenylglycinyl)- C-S 490.6phenylglycinyl}-amino-7-methyl- (Aldrich) amino-7-methyl-5,7-5,7-dihydro-6H- dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-241 5-{N′-(phenylacetyl)-L-leucinyl}-phenylacetic acid 5-(L-leucinyl)-amino-7- C-S 470.4amino-7-methyl-5,7-dihydro-6H- (Aldrich) methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one dibenz[b,d]azepin-6-one 7C-2425-{N′-(phenylacetyl)-L-2- phenylacetic acid 5-(L-2-cyclohexylglycinyl)-C-S 496.3 cyclohexylglycinyl}-amino-7- (Aldrich) amino-7-methyl-5,7-methyl-5,7-dihydro-6H- dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one 7C-243 5-{N′-(phenylacetyl)-L- phenylacetic acid5-(L-threoninyl)-amino-7- C-S 458.5 threoninyl}-amino-7-methyl-5,7-(Aldrich) methyl-5,7-dihydro-6H- dihydro-6H-dibenz[b,d]azepin-6-dibenz[b,d]azepin-6-one one 7C-244 5-{N′-(phenylacetyl)-L-alpha-(2-phenylacetic acid 5-(L-alpha-(2- C-S 496.2thienyl)glycinyl}-amino-7-methyl- (Aldrich) thienyl)glycinyl)-amino-7-5,7-dihydro-6H- methyl-5,7-dihydro-6H- dibenz[b,d]azepin-6-onedibenz[b,d]azepin-6-one

[2934] Additionally, the following procedures provide various carboxylicacid esters which can be hydrolyzed using General Procedures AC or BDbelow to afford the corresponding carboxylic acids. Coupling of theresulting carboxylic acids to the amines employed above using theGeneral Procedures set forth above provides for additional compoundswithin the scope of this invention.

General Procedure AA Reductive Amination

[2935] To a solution of the arylamine in ethanol in a hydrogenationflask was added 1 equivalent of the 2-oxocarboxylic acid ester (e.g.,pyruvate ester), followed by 10% palladium on carbon (25 weight percentbased on the arylamine). The reaction was hydrogenated at 20 psi H₂ on aParr shaker until complete reaction was indicated by tlc (30 minutes to16 hours). The reaction mixture was then filtered through a pad ofCelite 545 (available from Aldrich Chemical Company, Inc.) and strippedfree of solvent on a rotary evaporator. The crude product residue wasthen further purified via chromatography.

General Procedure AB First Transesterification Technique

[2936] A solution of 1-5 equivalents of the desired alcohol was added to1 equivalent of sodium hydride in toluene. After off-gassing had ceased,the compound to be transesterified, dissolved in toluene, was added.After 0.5 hours, the reaction was either heated to 40° C. and placedunder house vacuum (˜20 mmHg), or nitrogen was bubbled through thesolution while it was heated at 90° C. The reaction was followed by tlc,and when the reaction was complete the solution was cooled and quenchedwith water or 1M HCl, and in smaller scale reactions diluted with ethylacetate. The organic phase was extracted with saturated aqueous NaHCO₃,then washed with saturated aqueous NaCl and dried over MgSO₄. Thesolution was stripped free of solvent on a rotary evaporator, and thecrude product residue was then further purified by chromatography.Alternatively, the reaction mixture was worked-up by evaporation of thesolvents and direct chromatography of the crude mixture.

[2937] This procedure is particularly useful in the case of costlyand/or high boiling alcohols.

General Procedure AC Second Transesterification Technique

[2938] The compound to be transesterified was placed in a large excessof the desired alcohol. A catalytic amount of dry NaH was added, and thereaction was followed by tlc until the presence of starting material wasno longer detected. The reaction was quenched with a few milliliters of1N HCl, and after a few minutes of stirring saturated aqueous NaHCO₃ wasadded. The organic phase was washed with saturated aqueous NaCl anddried over MgSO₄. The solution was stripped free of solvent on a rotaryevaporator, and the crude product residue was then further purified bychromatography.

General Procedure AD Third Transesterification Technique

[2939] The compound to be transesterified was placed in a large excessof the desired alcohol. A catalytic amount of dry NaH was added, and thereaction was followed by tlc until the presence of starting material wasno longer detected. The reaction was quenched with a few milliliters of1N HCl, and after a few minutes of stirring saturated aqueous NaHCO₃ wasadded. The volume of the reaction mixture was reduced on a rotaryevaporator until the excess alcohol was removed and then the remainingresidue was taken up in ethyl acetate and additional water was added.The organic phase was washed with saturated aqueous NaCl and dried overMgSO₄. The solution was stripped free of solvent on a rotary evaporator,and the crude product residue was then further purified bychromatography.

[2940] This procedure is particularly employed in the case of lowboiling, inexpensive alcohols, miscible with water.

General Procedure AE O-Alkylation Technique

[2941] To a carboxylic acid compound (prepared, for example, byreductive amination via General Procedure AA to provide for the N-arylamino acid ester, followed by hydrolysis via Procedure AF) in DMF wasadded 1.5 equivalents K₂CO₃, followed by 1 equivalent of alkylatingagent (e.g., tert-butyl bromoacetate). The reaction was stirred at roomtemperature for 2 hours, then was quenched with water and extracted intoethyl acetate. The organic phase was washed with saturated aqueousNaHCO₃, water, and saturated aqueous NaCl, and was then dried overMgSO₄. The solution was stripped free of solvent on a rotary evaporatorto yield the crude product.

General Procedure AF Ester Hydrolysis to Free Acid

[2942] To a carboxylic ester compound (prepared, for example, byreductive amination via General Procedure AA to provide for the N-arylamino acid ester) in a 1:1 mixture of CH₃OH/H₂O was added 2-5equivalents of K₂CO₃. The mixture was heated to 50° C. for 0.5 to 1.5hours until tlc showed complete reaction. The reaction was cooled toroom temperature and the methanol was removed on a rotary evaporator.The pH of the remaining aqueous solution was adjusted to ˜2, and ethylacetate was added to extract the product. The organic phase was thenwashed with saturated aqueous NaCl and dried over MgSO₄. The solutionwas stripped free of solvent on a rotary evaporator to yield the crudeproduct.

General Procedure AG N-Heteroarylation of Alanine

[2943] A solution of 1.1 equivalents of L-alanine and 2 equivalents NaOHin DMSO was stirred at room temperature for 1 hour, then 1 equivalent of2-chlorobenzothiazole was added. The mixture was heated to 100° C. for 4hours, then cooled to room temperature and poured onto ice. The pH ofthe resulting aqueous solution was adjusted to ˜2, and the precipitatedsolid was removed by filtration. This solid was then dissolved in 1NNaOH and the resulting solution was filtered through a pad of Celite545. The pH of the filtrate was adjusted to ˜2, and the whiteprecipitate was removed by filtration and washed with water to yield thecrude product.

General Procedure AH EDC Coupling

[2944] To a 1:1 mixture of the desired acid and alcohol in CH₂Cl₂ at 0°C. was added 1.5 equivalents triethylamine, followed by 2.0 equivalentshydroxybenzotriazole monohydrate, then 1.25 equivalents ofethyl-3-(3-dimethylamino)-propyl carbodiimide-HCl (EDC). The reactionwas stirred overnight at room temperature, then transferred to aseparatory funnel and washed with water, saturated aqueous NaHCO₃, 1NHCl, and saturated aqueous NaCl, and was then dried over MgSO₄. Thesolution was stripped free of solvent on a rotary evaporator to yieldthe crude product.

General Procedure AI Oxime or Amine Coupling Technique

[2945] The trichlorophenyl ester (1 eq) of a carboxylic acid was stirredin DMF or THF. The oxime or amine (1.2 eq) was added and the mixture wasstirred at ambient temperature for 1-4 hours. In cases where thehydrochloride salt form of an amine was used, a suitable base such asN,N-diisopropylethylamine (1.2 eq) was also added. The resulting mixturewas concentrated under reduced pressure to yield a crude product whichwas used without purification or was purified by silica gelchromatography and/or crystallization.

General Procedure AJ Alkylation Technique

[2946] The amine (1 eq), the α-bromo ester (1.1 eq) and a suitable base(such as triethylamine) (2 eq) were stirred in chloroform. The resultingsolution was heated at reflux for 4-12 hours. After cooling, the mixturewas diluted with chloroform and washed with water. The organic portionwas dried (sodium sulfate) and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography.

General Procedure AK Oxime or Alcohol Coupling Technique

[2947] The carboxylic acid (1 eq) was stirred in a suitable solvent(such as THF, dioxane or DMF). An alcohol or oxime (1-5 eq) was added.EDC hydrochloride (1.2 eq) and hydroxybenzotriazole hydrate (1 eq) wereadded. A suitable base (such as 4-methylmorpholine or triethylamine)(0-1 eq) was added. A catalytic amount (0.1 eq) of4-dimethylaminopyridine was added. The mixture was stirred at ambienttemperature and under a dry atmosphere of nitrogen. After 20 hours, themixture was concentrated under reduced pressure. The resultingconcentrate was partitioned between ethyl acetate and water. The organicportion was separated and washed with aqueous sodium bicarbonate andbrine. The organic portion was dried (sodium sulfate) and concentratedunder reduced pressure. The crude product was used without purificationor was purified by silica gel chromatography and/or crystallization.

General Procedure AL EDC Coupling

[2948] The carboxylic acid was dissolved in methylene chloride. Theamino acid (1 eq.), N-methylmorpholine (5 eq.) and hydroxybenzotriazolemonohydrate (1.2 eq.) were added in sequence. A cooling bath was appliedto the round bottomed flask until the solution reached 0° C. At thattime, 1.2 eq. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) was added. The solution was allowed to stirovernight and come to room temperature under nitrogen pressure. Thereaction mixture was worked up by washing the organic phase withsaturated aqueous sodium carbonate, 0.M citric acid, and brine beforedrying with sodium sulfate. The solvents were then removed to yieldcrude product. Pure products were obtained by flash chromatography in anappropriate solvent.

General Procedure AM Triflate Displacement

[2949] To a 0° C. solution of iso-butyl R-(+)-lactate in CH₂Cl₂ wasadded 1.1 equivalents of trifluoromethanesulfonic anhydride. Afterstirring at room temperature for 20 min, 1.1 equivalents of 2,6-lutidinewas added and stirring was continued for 10 min. This solution was thentransferred to a flask containing 1 equivalent the arylamine and 1equivalent N,N-diisopropylethylamine in CH₂Cl₂ or CH₃NO₂ at 0° C. Thereaction was held overnight at room temperature and then stripped freeof solvent on a rotary evaporator. The residue was dissolved in ethylacetate, washed with 5% citric acid, followed by saturated aqueous NaCl,dried over magnesium sulfate or sodium sulfate and then the solution wasstripped free of solvent on a rotary evaporator to yield the crudeproduct, which was then purified by chromatography.

General Procedure AN BOC Removal

[2950] The BOC-protected compound was added to a 1:1 mixture of CH₂Cl₂and trifluoroacetic acid, and was stirred until tlc indicated completeconversion, typically 2h. The solution was then stripped to dryness andthe residue was taken up in ethyl acetate and extracted with dilute HCl.The acid reaction was neutralized and extracted with ethyl acetate. Theorganic phase was washed with saturated aqueous NaCl and dried overMgSO₄. The solution was stripped free of solvent on a rotary evaporatorto yield the product.

General Procedure AO Synthesis of Pyruvate Esters

[2951] To a mixture of pyruvic acid (8.8 g, 0.1 mol) (Aldrich) in 100 mLof benzene was added iso-butanol (14.82 g, 0.2 mol) and a catalyticamount of p-toluenesulfonic acid. The mixture was then refluxed using aDean Stark apparatus. After 4 hours, the reaction appeared to becomplete with the isolation of 1.8 g (0.1 mol) of water. The benzene andiso-butanol were removed on a rotary evaporator. The residue (14 g, 0.1mol), which was primarily the pyruvate iso-butyl ester by nmr [¹H-Nmr(CDCl₃): δ=4.0 (d, 2H), 2.5 (s, 3H), 2.0 (m, 1H), 1.0 (d, 6H)], was usedwithout further purification. By substituting other alcohols in place ofiso-butanol (e.g., ethanol, isopropanol, n-butanol, benzyl alcohol andthe like), other esters of pyruvic acid can be prepared in a similarmanner.

General Procedure AP Aromatic Nucleophilic Substitution ofFluorobenzenes

[2952] A mixture of 1.82 g (10 mmol) of D,L-alanine iso-butyl esterhydrochloride, the fluorobenzene (10 mmol) and 3 g of anhydrouspotassium carbonate in 10 mL of DMSO was stirred at 120° C. for 2-5hours. The reaction mixture was then cooled to room temperature anddiluted with 100 mL of ethyl acetate. The ethyl acetate extract waswashed with water (3×), dried over MgSO₄ and evaporated to dryness toafford the crude product, which was further purified by columnchromatography.

General Procedure AQ Fourth Transesterification Technique

[2953] The ester to be transesterified was dissolved in a large excessof the alcohol and 0.3 equivalents of titanium(IV) isopropoxide(Aldrich) was added. The reaction was followed by tlc until complete andthen the volatiles were removed at reduced pressure. The resulting crudematerial was then chromatographed to obtain the desired product.

General Procedure AR Synthesis on N-BOC Anilines

[2954] To a solution of the aniline in THF was added dropwise 1equivalent of di-tert-butyl dicarbonate (Aldrich) in THF and then 1.5equivalents of 10N aqueous sodium hydroxide at 0° C. After stirring atroom temperature for 16 hours, or heating at 80° C. for 3 hours, ifneeded, the reaction mixture was diluted with ether and washed withNaHCO₃, brine, dried over sodium sulfate and potassium carbonate,concentrated at reduced pressure and chromatographed to afford the N-BOCaniline.

General Procedure AS Oxime Ester Formation

[2955] The trichlorophenyl ester (1 eq.) was stirred in DMF or THF. Theoxime (1.2 eq.) was added and the mixture was stirred at ambienttemperature for 1 to 4 hours. The resulting mixture was concentratedunder reduced pressure and the residue was purified by silica gelchromatography and/or crystallization.

Example AA Synthesis of D,L-alanine iso-butyl ester hydrochloride

[2956] A mixture of 35.64 g (0.4 mol) of D,L-alanine (Aldrich), 44 mL(0.6 mol) of thionyl chloride (Aldrich) and 200 mL of iso-butanol wasrefluxed for 1.5 hours. The volatiles were removed at reduced pressureat 90° C. under reduced pressure to give the title compound as an oil,which was used without further purification.

[2957] NMR data was as follows:

[2958]¹H-nmr (CDCl₃): δ=8.72 (br s, 3H), 4.27 (q, J=7.4 Hz, 1H), 3.95(m, 2H), 1.96 (s, 1H), 1.73 (d, J=7.2 Hz, 3H), 0.92 (d, J=6.7 Hz, 6H).

[2959]¹³C-nmr (CDCl₃): δ=170.0, 72.2, 49.2, 27.5, 18.9, 16.1.

Example AB Synthesis of N-(3,4-dichlorophenyl)alanine

[2960] Using the procedure set forth in U.S. Pat. No. 3,598,859, thedisclosure of which is incorporated herein by reference in its entirety,N-(3,4-dichlorophenyl)alanine was prepared. Specifically, to a solutionof 3,4-dichloroaniline (1 equivalent) (Aldrich) in isopropanol (about500 mL per mole of 3,4-dichloroaniline) is added water (about 0.06 mLper mL of isopropanol) and 2-chloropropionic acid (2 equivalents)(Aldrich). This mixture is warmed to 40° C. and sodium bicarbonate (0.25equivalents) is added in successive portions before heating under refluxfor 4-5 days. After cooling, the reaction mixture is poured into waterand the unreacted 3,4-dichloroaniline is removed by filtration. Thefiltrate is acidified to pH 3-4 with concentrated hydrochloric acid andthe resultant precipitate is filtered, washed and dried to yield thetitle compound, m.p.=148-149° C.

[2961] Alternatively, following General Procedure AF above and usingN-(3,4-dichlorophenyl)alanine ethyl ester (from Example Al below), thetitle compound was prepared.

Example AC Synthesis of N-(3,5-difluorophenyl)alanine

[2962] Using the procedure set forth in U.S. Pat. No. 3,598,859,N-(3,5-difluorophenyl)alanine was prepared using 3,5-difluoroaniline(Aldrich) and 2-chloropropionic acid (Aldrich).

Example AD Synthesis of Iso-butyl 2-bromopropionate

[2963] To a mixture of iso-butanol and 1.0 equivalent of pyridine in drydiethyl ether was added dropwise 1.3 equivalents of 2-bromopropionylbromide at 0°C. After stirring at room temperature for 16 hours, thereaction was diluted with diethyl ether, washed with 1N HCl, water,aqueous NaHCO₃, brine and dried over magnesium sulfate or sodiumsulfate. Removal of the solvents at reduced pressure gave the titlecompound as a clear oil.

Example AE Synthesis of N-(2-naphthyl)alanine 2,4,5-trichlorophenylester

[2964] N-(2-Naphthyl)alanine methyl ester (5.0 g, 20.6 mmol) (fromExample A44 below) was dissolved in dioxane (100 mL). NaOH (30 mL, 1N)was added and the resulting solution was stirred for 1 hour. Thereaction mixture was concentrated under reduced pressure. The resultingsolid was dissolved in water and the aqueous mixture was washed withether. The aqueous portion was adjusted to pH 3 with 1N HCl andextracted with ethyl acetate. The organic extracts were dried overmagnesium sulfate or sodium sulfate and concentrated under reducedpressure to yield a white solid (4.35 g, 98%).

[2965] The resulting solid (4.35 g, 20 mmol) was dissolved indichloromethane (300 mL). 2,4,5-Trichlorophenol (4.9 g, 25 mmol)(Aldrich) was added followed by dicyclohexylcarbodiimide (25 mL, 1M indichloromethane) (Aldrich). After stirring for 18 hours, the mixture wasfiltered and concentrated to provide an oil which was purified bychromatography on silica gel using chloroform as the eluant (R_(f)=0.6).The title compound was obtained as a thick oil which slowlycrystallized.

Example Al Synthesis of N-(3,4-dichlorophenyl)alanine ethyl ester

[2966] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the titlecompound was prepared as an oil. The reaction was monitored by tlc onsilica gel (Rf=0.4 in 25% EtOAc/hexanes) and purification was bypreparative plate chromatography (silica gel using 25% EtOAc/hexanes asthe eluant).

[2967] NMR data was as follows:

[2968]¹H-nmr (CDCl₃): δ=7.2 (d, 1H); 6.7 (d, 1H,); 6.4 (dd, 1H); 4.30(bs, 1H); 4.2 (q, 2H); 4.1 (q, 1H); 1.5 (d, 3H); 1.3 (t, 3H).

[2969]¹³C-nmr (CDCl₃): δ=175; 146.7; 133; 131; 121; 114.9; 112.6; 72.0;52.4; 28.3; 19.5.

[2970] C₁₁H₁₃Cl₂NO₂ (MW=262.14).

Example A2 Synthesis of N-(3-trifluoromethyl4-chlorophenyl)alanine ethylester

[2971] Following General Procedure AA above and using4-chloro-3-(trifluoromethyl)aniline (Aldrich) and ethyl pyruvate(Aldrich), the title compound was prepared.

[2972] Analysis: Calc.: C, 48.74; H, 4.43; N, 4.74. Found: C, 48.48; H,4.54; N, 4.94.

[2973] C₁₂H₁₃F₃ClNO₂ (MW=295.69); mass spectroscopy (MH⁺) 295.

Example A3 Synthesis of N-(3,5-dichlorophenyl)alanine ethyl ester

[2974] Following General Procedure AA above and using3,5-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the titlecompound was prepared.

[2975] Analysis: Calc.: C, 50.40; H, 5.00; N, 5.34. Found: C, 50.50; H,5.06; N, 5.25.

[2976] C₁₁H₁₃Cl₂NO₂ (MW=262.14); mass spectroscopy (MH⁺) NA.

Example A4 Synthesis of N-(3,4-difluorophenyl)alanine ethyl ester

[2977] Following General Procedure AA above and using3,4-difluoroaniline (Aldrich) and ethyl pyruvate (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc on silica gel(Rf=0.4 in 25% EtOAc/hexanes) and purification was by preparative platechromatography (silica gel using 25% EtOAc/hexanes as the eluant).

[2978] NMR data was as follows:

[2979]¹H-nmr (CDCl₃): δ=7.4 (m, 1H), 6.8 (d, 1H), 6.5 (m, 1H), 4.30 (bs,1H), 4.2 (q, 2H), 4.1 (q, 1H), 1.5 (d, 3H), 1.3 (t, 3H).

[2980]¹³C-nmr (CDCl₃): δ=175, 146.7, 135, 132, 125, 116, 113, 72, 52,28, 19.

[2981] C₁₁H₁₃F₂NO₂ (MW=229.23); mass spectroscopy (MH⁺) 230.

Example A5 Synthesis of N-(3,4-dichlorophenyl)alanine benzyl ester

[2982] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and benzyl pyruvate (prepared by followingGeneral Procedure AO above using benzyl alcohol in place ofiso-butanol), the title compound was prepared as an oil. The reactionwas monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) andpurification was by preparative plate chromatography (silica gel using25% EtOAc/hexanes as the eluant).

[2983] NMR data was as follows:

[2984]¹H-nmr (CDCl₃): δ=7.18 (d, 1H); 7.0 (m, 5H); 6.6 (d, 1H,); 6.4(dd, 1H); 5.1 (s, 2H); 4.30 (bs, 1H); 4.08 (q, 1H); 1.94 (m, 1H); 1.47(d, 3H); 0.91 (d,6H).

[2985]¹³C-nmr (CDCl₃): δ=174.5; 146.7; 133.5; 131.3; 121.3; 120.1;114.9; 113.6; 72.0; 60.1; 52.4; 28.3; 19.5; 19.3.

[2986] C₁₆H₁₅Cl₂NO₂ (MW=324.31); mass spectroscopy (MH⁺) 325.

Example A6 Synthesis of N-(3,4-dichlorophenyl)alanine iso-butyl ester

[2987] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared byfollowing General Procedure AO above), the title compound was preparedas an oil. The reaction was monitored by tlc on silica gel (Rf=0.55 in25% EtOAc/hexanes) and purification was by preparative platechromatography (silica gel using 25% EtOAc/hexanes as the eluant).

[2988] NMR data was as follows:

[2989]¹H-nmr (CDCl₃): δ=7.18 (d, 1H, J=8.7 Hz), 6.66 (d, 1H, J=2.7 Hz),6.43 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.30 (bs, 1H), 4.08 (q, 1H, J=6.9Hz), 1.94 (sept, 1H, J=6.7 Hz), 1.47 (d, 3H J=6.9 Hz), 0.91 (d, 6H,J=6.6 Hz).

[2990]¹³C-nmr (CDCl₃) δ=174.5, 146.7, 133.5, 131.3, 121.3, 114.9, 113.6,72.0, 52.4, 28.3, 19.5, 19.3.

[2991] C₁₃H₁₇C₂NO₂ (MW=290.19); mass spectroscopy (MH⁺) 290.

Example A7 Synthesis of N-(3,4-dichlorophenyl)alanine iso-propyl ester

[2992] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and isopropyl pyruvate (prepared byfollowing General Procedure AO above using isopropanol in place ofiso-butanol), the title compound was prepared as an oil. The reactionwas monitored by tlc on silica gel (Rf=0.4 in 25% EtOAc/hexanes) andpurification was by preparative plate chromatography (silica gel using25% EtOAc/hexanes as the eluant).

[2993] NMR data was. as follows:

[2994]¹H-nmr (CDCl₃): δ=7.18 (d, 1H); 6.66 (d, 1H,); 6.43 (dd, 1H); 4.30(bs, 1H); 4.08 (m, 1H); 1.94 (m, 1H); 1.47 (d, 3H); 0.91 (d, 6H).

[2995]¹³C-nmr (CDCl₃): δ=174.5; 146.7; 133.5; 131.3; 121.3; 114.9;113.6; 72.0; 52.4; 19.5.

[2996] C₁₂H₁₅C₂NO₂ (MW=276.16); mass spectroscopy (MH⁺) 277.

Example A8 Synthesis of N-(3,4-dichlorophenyl)alanine n-butyl ester

[2997] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and n-butyl pyruvate (prepared byfollowing General Procedure AO above using n-butanol in place ofiso-butanol), the title compound was prepared. The reaction wasmonitored by tlc on silica gel (Rf=0.7 in 25% EtOAc/hexanes) andpurification was by preparative plate chromatography (silica gel using25% EtOAc/hexanes as the eluant).

[2998] NMR data was as follows:

[2999]¹H-nmr (CDCl₃): δ=7.18 (d, 1H); 6.66 (d, 1H,); 6.43 (dd, 1H); 4.30(bs, 1H); 4.2 (m, 2H); 4.08 (q, 1H); 1.94 (m, 1H); 1.47 (m, 4H); 0.91(t, 3H).

[3000]¹³C-nmr (CDCl₃): δ=174.5; 146.7; 133.5; 131.3; 121.3; 114.9;113.6; 72.0; 52.4; 28.3; 20.2; 19.5.

[3001] C₁₃H₁₇C₂NO₂ (MW=290.19); mass spectroscopy (MH⁺) 291.

Example A9 Synthesis of N-(3,4-dichlorophenyl)alanine methyl ester (R,Sisomers)

[3002] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and methyl pyruvate (Aldrich), the titlecompound was prepared as an oil. The reaction was monitored by tlc onsilica gel (Rf=0.55 in 25% EtOAc/hexanes) and purification was by flashchromatography (silica gel using 25% EtOAc/hexanes as the eluant).

[3003] NMR data was as follows:

[3004]¹H-nmr (CDCl₃): δ=7.19 (d, J=8.73 Hz, 1H), 6.66 (d, J=2.75 Hz,1H), 6.43 (dd, J=8.73 Hz, 2.80 Hz, 1H), 4.25 (bd, J=8.25 Hz, 1H), 4.08(m, 1H), 3.76 (s, 3H), 1.47 (d, J=6.90 Hz).

[3005]¹³C-nmr (CDCl₃) δ=174.35, 145.96, 132.87, 130.70, 120.76, 114.38,112.90, 52.43, 51.70, 18.67.

[3006] C₁₀H₁₁Cl₂NO₂ (MW=248.11); mass spectroscopy (MH⁺) 247.

Example A10 Synthesis of N-(3,4-dichlorophenyl)alanine cyclopentyl ester

[3007] Following transesterification General Procedure AB above andusing N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above)and cyclopentanol (Aldrich), the title compound was prepared as an oil.The reaction was monitored by silica gel tlc (Rf=0.66 in 25%EtOAc/hexanes). Purification was by preparative plate chromatography(silica gel using 25% EtOAc/hexanes as the eluant).

[3008] NMR data was as follows:

[3009]¹H-nmr (CDCl₃): δ=7.19 (d, 1H, J=8.7 Hz), 6.66 (d, 1H, J=2.7 Hz),6.43 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 5.22 (m, 1H), 4.27 (d, 1H, J=8.1 Hz),4.02 (quint, 1H, J=7.5 Hz), 1.74 (m, 8H), 1.43 (d, 3H, J=6.9 Hz).

[3010]¹³C-nmr (CDCl₃): δ=174.3, 146.7, 133.4, 131.2, 121.2. 114.9,113.7, 78.9, 52.5, 33.2, 24.2, 24.1, 19.1.

[3011] C₁₄H₁₇C₂NO₂ (MW=302.20); mass spectroscopy (MH⁺) 301.

Example A11 Synthesis of N-(3,4-dichlorophenyl)alanine n-propyl ester

[3012] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and n-propyl pyruvate (prepared byfollowing General Procedure AO above using n-propanol in place ofiso-butanol), the title compound was prepared as an oil. The reactionwas monitored by tlc on silica gel (Rf=0.5 in 25% EtOAc/hexanes) andpurification was by preparative plate chromatography (silica gel using25% EtOAc/hexanes as the eluant).

[3013] NMR data was as follows:

[3014]¹H-nmr (CDCl₃): δ=7.2 (d, 1H); 6.6 (d, 1H); 6.4 (dd, 1H); 4.30(bs, 1H); 4.2 (q, 2H); 4.08 (q, 1H); 1.94 (m, 2H); 1.5 (d, 3H); 0.95 (t,3H).

[3015]¹³C-nmr (CDCl₃): δ=178; 144.7; 130.2; 120.62; 115.11; 71.82;52.90.

[3016] C₁₂H₁₅C₂NO₂ (MW=276.16); mass spectroscopy (MH⁺) 277.

Example A12 Synthesis of N-(3,4-dichlorophenyl)alanine allyl ester

[3017] Following transesterification General Procedure AB above andusing N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above)and allyl alcohol (Aldrich), the title compound was prepared as an oil.The reaction was monitored by silica gel tlc (Rf=0.62 in 25%EtOAc/hexanes). Purification was by preparative plate chromatography(silica gel using 25% EtOAc/hexanes as the eluant).

[3018] NMR data was as follows:

[3019]¹H-nmr (CDCl₃): δ=7.19 (d, 1H, J=8.7 Hz), 6.67 (d, 1H, J=2.8 Hz),6.44 (dd, 1H, J=8.7 Hz, J=2.8 Hz), 5.90 (m, 1H), 5.30 (m, 2H), 4.64 (m,2H) 4.26 (m, 1H, 4.10 (m, 1H), 1.48 (d, 3H, J=6.9 Hz).

[3020]¹³C-nmr (CDCl₃): δ=174.1, 146.6, 133.5, 132.1, 131.3, 121.4 119.6,115.0, 113.6, 66.5, 52.4, 19.3.

[3021] C₁₂H₁₃Cl₂NO₂ (MW=274.15); mass spectroscopy (MH⁺) 273.

Example A13 Synthesis of N-(3,4-dichlorophenyl)alanine 4-methylpentylester

[3022] Following transesterification General Procedure AB above andusing N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above)and 4-methylpentanol (Aldrich), the title compound was prepared as anoil. The reaction was monitored by silica gel tlc (Rf=0.70 in 25%EtOAc/hexanes). Purification was by preparative plate chromatography(silica gel using 25% EtOAc/hexanes as the eluant).

[3023] NMR data was as follows:

[3024]¹H-nmr (CDCl₃): δ=7.18 (d, 1H, J=8.7 Hz), 6.66 (d, 1H, J=2.7 Hz),6.43 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.28 (m, 1H), 4.10 (m, 3H), 1.55 (m,6H), 1.19 (m, 2H), 0.87 (d, 3H, J=6.6 Hz).

[3025]¹³C-nmr (CDCl₃): δ=174.6, 146.7, 133.4, 131.3, 121.3, 115.0,113.6, 66.4, 52.4, 35.4, 28.2, 27.0, 23.0, 19.3.

[3026] C₁₅H₂₁Cl₂NO₂ (MW=318.25); mass spectroscopy (MH⁺) 317.

Example A14 Synthesis of N-(3,4-dichlorophenyl)alanine2,2-dimethyl-1,3-dioxolane-4-methyl ester

[3027] Following transesterification General Procedure AB above andusing N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above)and 2,2-dimethyl-1,3-dioxolane-4-methanol (solketal) (Aldrich), thetitle compound was prepared as a mixture of diastereomers. The reactionwas monitored by silica gel tlc (Rf=0.32 in 25% EtOAc/hexanes).Purification was by preparative plate chromatography (silica gel using25% EtOAc/hexanes as the eluant).

[3028] NMR data was as follows:

[3029]¹H-nmr (CDCl₃): δ=7.19 (d, 1H, J=8.7 Hz), 6.66 (d, 1H, 2.7 Hz),6.43 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.22 (m, 6H), 3.70 (m, 1H), 1.43 (m,9H).

[3030]¹³C-nmr (CDCl₃): δ=174.34, 174.32, 146.5, 133.5, 131.3, 121.5,115.0, 113.6, 110.52, 110.51, 73.97, 73.89, 66.6, 66.01, 65.95, 52.42,52.37, 27.3, 25.8, 19.3.

[3031] C₁₅H₁₉Cl₂NO₄ (MW=348.23); mass spectroscopy (MH⁺) 347.

Example A 15 Synthesis of N-(3,4-dichlorophenyl)alanine cyclohexylmethylester

[3032] Following transesterification General Procedure AB above andusing N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above)and cyclohexylmethanol (Aldrich), the title compound was prepared.

[3033] NMR data was as follows:

[3034]¹H-nmr (CDCl₃): δ=7.19 (d, 1H), 6.68 (d, 1H), 6.45 (dd, 1H), 4.26(bd, 1H), 4.10 (m, 1H), 3.95 (d, 2H), 1.70-1.55 (m, 6H), 1.50 (d, 3H),1.35-0.85 (m, 5H).

[3035]¹³C-nmr (CDCl₃): δ=174.58, 146.72, 133.48, 131.27, 121.34, 114.98,113.72, 71.06, 52.52, 37.68, 30.10, 26.83, 26.17, 19.32.

[3036] C₁₅H₂₁Cl₂NO₂ (MW=318.25); mass spectroscopy (MH⁺) 317.

Example A16 Synthesis of N-(3,4-dichlorophenyl)alaninetert-butyloxycarbonylmethyl ester

[3037] Following General Procedure AE above and usingN-(3,4-dichlorophenyl)alanine (from Example AB above) and tert-butylbromoacetate (Aldrich), the title compound was prepared as a solid. Thereaction was monitored by silica gel tlc (Rf=0.57 in 25% EtOAc/hexanes).Purification was by recrystallization from ethanol.

[3038] NMR data was as follows:

[3039]¹H-nmr (CDCl₃): δ=7.19 (d, 1H), 6.68 (d, 1H), 6.45 (dd, 1H), 4.55(m, 2H), 4.20 (m, 2H), 1.55 (d, 3H), 1.45 (s, 9H).

[3040]¹³C-nmr (CDCl₃): δ=173.9, 166.9, 146.5, 133.5, 131.3, 115.1,113.6, 83.4, 62.2, 52.2, 28.6, 19.3.

[3041] C₁₅H₁₉Cl₂NO₄ (MW=348.23); mass spectroscopy (MH⁺) 347.

Example A17 Synthesis of N-(3,4-dichlorophenyl)leucine iso-butyl ester

[3042] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and iso-butyl 4-methyl-2-oxopentanoate(prepared by following General Procedure AO above using4-methyl-2-oxovaleric acid (Fluka) and iso-butanol), the title compoundwas prepared as an oil. The reaction was monitored by tlc on silica gel(Rf=0.6 in 25% EtOAc/hexanes) and purification was by preparative platechromatography (silica gel using 25% EtOAc/hexanes as the eluant).

[3043] NMR data was as follows:

[3044]¹H-nmr (CDCl₃): δ=7.2 (d, 1H); 6.5 (d, 1H); 6.4 (dd, 1H); 4.30(bs, 1H); 4.08 (q, 1H); 3.8(m, 2H); 1.8 (m, 3H); 0.91 (m, 12H).

[3045]¹³C-nmr (CDCl₃): δ=174.5; 146.7; 133.5; 131.3; 121.3; 114.9;113.6; 72.0; 52; 28.3; 20.1; 19.5.

[3046] C₁₆H₂₃Cl₂NO₂ (MW=332.27); mass spectroscopy (MH⁺) 333.

Example A18 Synthesis of 2-[N-(3,4-dichlorophenyl)amino]pentanoic acidiso-butyl ester

[3047] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxopentanoate (prepared byfollowing General Procedure AO above using 2-oxovaleric acid (Fluka) andiso-butanol), the title compound was prepared as an oil. The reactionwas monitored by tlc on silica gel (Rf=0.5 in 25% EtOAc/hexanes) andpurification was by preparative plate chromatography (silica gel using25% EtOAc/hexanes as the eluant).

[3048] NMR data was as follows:

[3049]¹H-nmr (CDCl₃): δ=7.2 (d, 1H); 6.6 (d, 1H); 6.4 (dd, 1H); 4.3 (d,1H); 3.8 (m, 3H); 1.9 (m, 6H); 1.0 (t, 3H), 0.9 (m, 6H).

[3050]¹³C-nmr (CDCl₃): δ=178; 144.7; 130.2; 120.62; 115.11; 71.82;52.90; 28.30; 19.53.

[3051] C₁₅H₂₁Cl₂NO₂ (MW=318.3); mass spectroscopy (MH⁺) 319.

Example A19 Synthesis of N-(4-cyanophenyl)alanine iso-butyl ester

[3052] Following General Procedure AP above and using4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl esterhydrochloride (from Example AA above), the title compound was preparedas an oil. The product was recovered by column chromatography on silicagel using 1:5 EtOAc/hexanes as the eluant.

[3053] NMR data was as follows:

[3054]¹H-nmr (CDCl₃): δ=7.44 (d, J=8.8 Hz, 2H), 6.57 (d, J 8.8 Hz, 2H),4.74 (d, J=8.1 Hz, 1H), 4.18 (t, J=7.4 Hz, 1H), 3.95 (m, 2H), 1.94 (m,1H), 1.51 (d, J=6.9 Hz, 3H), 0.91 (d, J=6.7 Hz, 6H).

[3055]¹³C-nmr (CDCl₃): δ=173.4, 149.7, 133.8, 120.1, 112.7, 99.8, 71.6,51.2, 27.7, 18.9, 18.6.

[3056] C₁₄H₁₈N₂O₂ MW=246.31; mass spectroscopy (MH⁺) 247.

Example A20 Synthesis of N-(3-chloro-4-cyanophenyl)alanine iso-butylester

[3057] Following General Procedure AP above and using2-chloro-4-fluorobenzonitrile (Aldrich) and D,L-alanine iso-butyl esterhydrochloride (from Example AA above), the title compound was prepared.The product was recovered by column chromatography on silica gel using1:5 EtOAc/hexanes as the eluant.

[3058] NMR data was as follows:

[3059]¹H-nmr (CDCl₃): δ=7.40 (d, J=8.5 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H),6.48 (dd, J=2.4, 8.6 Hz, 1H), 4.90 (d, J=7.6 Hz, 1H), 4.16 (quintet,J=7.1 Hz, 1H), 3.96 (dd, J=2.2, 6.7 Hz, 2H), 1.97 (m, 1H), 1.51 (d,J=7.0 Hz, 3H), 0.93 (d, J=6.7 Hz, 6H).

[3060]¹³C-nmr (CDCl₃): δ=173.0, 150.4, 138.3, 134.9, 117.3, 112.82111.3, 100.6, 71.7, 51.1, 27.7, 18.9, 18.4.

[3061] C₁₄H₁₇N₂O₂Cl MW=280.76; mass spectroscopy (MH⁺) 281.

Example A21 Synthesis of N-(3,4-dichloro)alanine iso-butyl ester (Sisomer)

[3062] Following General Procedure AM above and using3,4-dichloroaniline (Aldrich) and iso-butyl R-(+)-lactate (Aldrich), thetitle compound was prepared as an oil. The reaction was monitored bysilica gel tlc (Rf=0.55 in 25% EtOAc/hexanes). Purification was columnchromatography.

[3063] NMR data was as follows:

[3064]¹H-nmr (CDCl₃): δ=7.19 (d, J=8.73, 1H), 6.67 (d, J=2.75, 1H), 6.45(dd, J=8.73, J=2.75, 1H), 4.28 (bd, J=8.36, 1H), 4.09 (quint, 1H), 3.94(d, J=6.66, 2H), 1.95 (hept, J=6.71, 1H), 1.49 (d, J=6.90, 3H), 0.92 (d,J=6.04, 6H).

[3065]¹³C-nmr (CDCl₃): δ=174.57, 146.67, 133.47, 131.28, 121.29, 114.93,113.63, 71.01, 52.43, 28.30, 19.55, 19.33.

[3066] C₁₃H₁₇Cl₂NO₂ (MW=290.19); mass spectroscopy (MH⁺) 290.

Example A22 Synthesis of N-(3,4-dichloro)alaninetetrahydrofuran-3-yl-methyl ester

[3067] Following transesterification General Procedure AB above andusing N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above)and tetrahydro-3-furanmethanol (Aldrich), the title compound wasprepared as an oil. The reaction was monitored by silica gel tlc(Rf=0.33 in 25% EtOAc/hexanes). Purification was by preparative platechromatography (silica gel using 25% EtOAc/hexanes as the eluant).

[3068] NMR data was as follows:

[3069]¹H-nmr (CDCl₃): δ=7.18 (d, 1H, J=8.7 Hz), 6.65 (d, 1H, J=2.7 Hz),6.42 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.30 (m, 1H), 4.09 (m, 3H), 3.78 (m,3H), 3.53 (m, 1H), 2.56 (m, 1H), 1.94 (m, 1H), 1.58 (m, 1H), 1.46 (d,3H, J =6.9 Hz).

[3070]¹³C-nmr (CDCl₃): δ=174.5, 146.6, 133.5, 131.3, 121.4, 114.9,113.6, 70.86, 70.83, 68.2, 67.31, 67.29, 52.4, 38.7, 29.36, 29.33, 19.2.

[3071] C₁₄H₁₇Cl₂NO₃ (MW=318.20); mass spectroscopy (MH⁺) 318.

Example A23 Synthesis of N-(3,5-dichlorophenyl)alanine n-propyl ester

[3072] Following General Procedure AA above and using3,5-dichloroaniline (Aldrich) and n-propyl pyruvate (which can beprepared by following General Procedure AO above using n-propanol inplace of iso-butanol), the title compound could be prepared.

Example A24 Synthesis of 2-[N-(3,4-dichlorophenyl)amino]butanoic acidiso-butyl ester

[3073] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxobutanoate (prepared byfollowing General Procedure AO above using 2-oxobutyric acid (Aldrich)and iso-butanol), the title compound was prepared as an oil. Thereaction was monitored by tlc on silica gel (Rf=0.3 in 25%EtOAc/hexanes) and purification was by preparative plate chromatography(silica gel using 25% EtOAc/hexanes as the eluant).

[3074] NMR data was as follows:

[3075]¹H-nmr (CDCl₃): δ=7.2 (d, 1H); 6.6 (d, 1H); 6.4 (dd, 1H); 4.3 (d,1H); 3.8 (m, 3H); 1.9 (m, 3H); 1.0 (t, 3H); 0.9(m, 6H).

[3076]¹³C-nmr (CDCl₃): δ=178; 144.7; 130.2; 120.62; 115.11; 71.82;52.90; 28.30; 20.5; 19.53.

[3077] C₁₄H₁₉Cl₂NO₂ (MW=304.22); mass spectroscopy (MH⁺) 305.

Example A25 Synthesis of N-(4-chlorophenyl)alanine iso-butyl ester

[3078] Following General Procedure AA above and using 4-chloroaniline(Aldrich) and iso-butyl pyruvate (prepared by following GeneralProcedure AO above), the title compound was prepared as an oil. Thereaction was monitored by tlc on silica gel (Rf=0.6 in 25%EtOAc/hexanes) and purification was by preparative plate chromatography(silica gel using 25% EtOAc/hexanes as the eluant).

[3079] NMR data was as follows:

[3080]¹H-nmr (CDCl₃): δ=7.18 (d, 2H), 6.66 (d, 2H), 4.30 (bs, 1H), 4.08(q, 1H), 1.94 (sept, 1H), 1.47 (d, 3H), 0.91 (d, 6H).

[3081]¹³C-nmr (CDCl₃): δ=174.5, 146.7, 133.5, 131.3, 121.3, 114.9,113.6, 72.0, 52.4, 28.3, 19.5, 19.3.

[3082] C₁₃H₁₈ClNO₂ (MW=255.75); mass spectroscopy (MH⁺) 256.

Example A26 Synthesis of N-(3,5-dichlorophenyl)alanine iso-butyl ester

[3083] Following General Procedure AA above and using3,5-dichloroaniline (Aldrich) and iso-butyl pyruvate (prepared byfollowing General Procedure AO above), the title compound was preparedas an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in25% EtOAc/hexanes) and purification was by preparative platechromatography (silica gel using 25% EtOAc/hexanes as the eluant).

[3084] NMR data was as follows:

[3085]¹H-nmr (CDCl₃): δ=7.18 (d, 2H), 6.66 (m, 1H), 4.30 (bs, 1H), 4.08(q, 1H), 1.94 (m, 1H), 1.47 (d, 3H), 0.91 (d, 6H).

[3086]¹³C-nmr (CDCl₃): δ=175; 146.7; 133; 131; 121; 114.9; 112.6; 72.0;52.4; 28.3; 19.5.

[3087] C₁₃H₁₇Cl₂NO₂ (MW=290.2); mass spectroscopy (MH⁺) 291.

Example A27 Synthesis of N-(4-ethylphenyl)alanine methyl ester

[3088] A solution of 0.68 g (5 mmol) of 4′-aminoacetophenone (Aldrich),0.60 mL of 90% methyl pyruvate (Aldrich) and 0.05 g (0.25 mmol) ofp-toluenesulfonic acid in ethanol was hydrogenated in the presence of acatalytic amount of 10% Pd/C at from 30 to 15 psi of hydrogen for 16hours. The catalyst was removed by filtering the reaction mixturethrough Celite and the solvent was evaporated to provide the crudeproduct. The product was purified by column chromatography (silica gelusing 1:9 EtOAc/hexanes as the eluant) to provide the title compound.

[3089] NMR data was as follows:

[3090]¹H-nmr (CDCl₃): δ=1.19 (t, J=7.6 Hz, 3H), 1.47 (d, J=6.8 Hz, 3H),2.54 (q, J=7.6 Hz, 2H), 3.74 (s, 3H), 4.04 (bs, 1H), 4.13 (m, 1H), 6.57(d, J=8.5 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H).

[3091]¹³C-nmr (CDCl₃): δ=15.8, 18.0, 27.9, 52.17, 52.19, 113.5; 128.6,134.1, 144.4, 175.3.

[3092] C₁₂H₁₇NO₂ MW=207.27; mass spectroscopy (MH⁺) 208.

Example A28 Synthesis of N-(4-(1-ethoxy)ethylphenyl)alanine methyl ester

[3093] Following the procedure for Example A27 above, the title compoundwas isolated as another reaction product by column chromatography(silica gel using 1:9 EtOAc/hexanes as the eluant).

[3094] NMR data was as follows:

[3095]¹H-nmr (CDCl₃): δ=1.15 (t, J=7.0 Hz, 3H), 1.40 (d, J=6.5 Hz, 3H),1.47 (d, J=6.1 Hz, 3H), 3.31 (q, J=5.1 Hz, 2H), 3.74 (s, 3H), 4.14 (m,2H 4.29 (q, J=6.4 Hz, 1H), 6.57 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.4 Hz,2H).

[3096]¹³C-nmr (CDCl₃): δ=15.4, 19.0, 23.9, 51.9, 52.2, 63.4, 77.3,113.1, 127.3, 133.6, 145.8, 175.1.

[3097] C₁₄H₁₂NO₃ MW=251.33; mass spectroscopy (MH⁺) 251.

Example A29 Synthesis of N-(3,4-dichloro)alanine 2,2-dimethylpropylester (R,S isomers)

[3098] Following transesterification General Procedure AQ above andusing N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above)and neopentyl alcohol (Aldrich), the title compound was prepared. Thereaction was monitored by silica gel tlc (Rf=0.72 in 25% EtOAc/hexanes).Purification was by flash chromatography (silica gel using 25%EtOAc/hexanes as the eluant).

[3099] NMR data was as follows:

[3100]¹H-nmr (CDCl₃): δ=7.19 (d, 1H, J=8.7 Hz), 6.68 (d, 1H, J=2.7 Hz),6.45 (dd, 1H, J=8.7 Hz, J=2.7 Hz), 4.29 (m, 1H), 4.11 (m, 1H), 3.85 (m,2H), 1.49 (d, 3H, J=6.9 Hz), 0.93 (s, 9H).

[3101]¹³C-nmr (CDCl₃): δ=174.6, 146.7, 133.5, 131.3, 121.3, 114.9,113.7, 75.2, 52.4, 32.0, 26.9, 19.4.

[3102] C₁₄H₁₉Cl₂NO₂ (MW=304.22); mass spectroscopy (MH⁺) 303.

Example A30 Synthesis of N-(3,4-dichlorophenyl)glycine iso-butyl ester

[3103] 3,4-Dichloroaniline (Aldrich) was treated with di-tert-butyldicarbonate (Aldrich) using conventional procedures to produce the N-BOCaniline. The N-BOC aniline was treated with sodium hydride in THF andthen with iso-butyl 2-bromoacetate (from Example AD above) to producethe N-BOC N-(3,4-dichlorophenyl)glycine iso-butyl ester. The BOC groupwas then removed using General Procedure AN above to afford the titlecompound. The reaction was monitored by tlc on silica gel (Rf=0.78 in50% EtOAc/hexanes) and purification was by preparative platechromatography (silica gel using 50% EtOAc/hexanes as the eluant).

[3104] NMR data was as follows:

[3105]¹H-nmr (CDCl₃): δ=7.19 (dd, J=4.1, 4.7, 3.4, 1H); 6.65 (d, J=2.7,1H); 6.44 (dd, J=2.7, 4.5, 4.2, 1H): 4.4 (m, 1H): 3.97 (dd, J=3.6, 3.0,2.3, 2H); 3.87 (s, 2H); 1.9 (m, 1H); 0.93 (d, J=6.7, 6H).

[3106]¹³C-nmr (CDCl₃): δ=171.2, 147.0, 133.5, 131.3, 121.2, 114.5,113.3, 72.2, 46.0, 28.2, 19.6.

[3107] C₁₂H₁₅Cl₂NO₂ (MW=276); mass spectroscopy (MH⁺) 277.

Example A31 Synthesis of N-(3,4-dichlorophenyl)alanine 2-ethylbutylester

[3108] Following General Procedure AA above and using3,4-dichloroaniline (Aldrich) and 2-ethylbutyl pyruvate (prepared byfollowing General Procedure AO above using 2-ethylbutanol (Aldrich) inplace of iso-butanol), the title compound was prepared as an oil. Thereaction was monitored by tlc on silica gel (Rf=0.6 in 25%EtOAc/hexanes) and purification was by preparative plate chromatography(silica gel using 25% EtOAc/hexanes as the eluant).

[3109] NMR data was as follows:

[3110]¹H-nmr (CDCl₃): δ=7.2 (d, 1H); 6.6 (d, 1H); 6.4 (dd, 1H); 4.2 (t,2H); 4.1 (q, 1H); 1.5 (d, 3H); 1.4 (m, 4H); 1.0 (m, 6H).

[3111]¹³C-nmr (CDCl₃): δ=178; 144.7; 130.2; 120.62; 115.11; 70.7; 51.90;26.3; 19.53, 18.5.

[3112] C₁₅H₂₁Cl₂NO₂ (MW=318.25); mass spectroscopy (MH⁺) 319.

Example A32 Synthesis of N-(3-chloro-4-iodophenyl)alanine iso-butylester

[3113] Following General Procedure AR above and using3-chloro-4-iodoaniline (Aldrich), N-BOC-3-chloro-4-iodoaniline wasprepared. To a stirred slurry of 5.0 equivalents of sodium hydride inDMF was added 1.0 equivalent of N-BOC-3-chloro-4-iodoaniline and then1.1 equivalents of iso-butyl 2-bromopropionate (from Example AD above)were slowly added. The reaction was heated to 100° C. for 10 hours,cooled, diluted with dichloromethane and washed with cold 1N HCl, waterand brine. The solvents were removed at reduced pressure and the residuewas chromatographed to provide N-BOC-N-(3-chloro-4-iodophenyl)alanineiso-butyl ester as a clear oil. Following General Procedure AN above,the BOC group was removed from N-BOC-N-(3-chloro-4-iodophenyl)alanineiso-butyl ester to provide the title compound. The BOC-removal reactionwas monitored by tlc on silica gel (Rf=0.58 in 30% EtOAc/hexanes) andpurification was by preparative plate chromatography (silica gel using30% EtOAc/hexanes as the eluant). The compound was further purified bychromatography on an HPLC chiral column (Chiralcel OD).

[3114] NMR data was as follows:

[3115]¹H-nmr (CDCl₃): δ=7.52 (d, J=8.7, 1H); 6.72 ( d, J=2.7, 1H); 6.25(dd, J=2.7, 5.9, 2.7, 1H); 4.35 (d, J=6.6, 1H): 4.08 (quintex, J=7.2,6.7, 1H); 3.93 (d, J=6.7, 2H): 1.94 (m, 1H); 1.47 (d, J=6.9, 3H); 0.92(d, J=6.9, 6H).

[3116]¹³C-nmr (CDCl₃): δ=174.5, 148.3, 140.7, 139.5, 114.4, 114.3, 82.6,72.0, 52.2, 28.3, 19.6, 19.3.

[3117] C₁₃H₁₇ClNO₂ (MW=381.5); mass spectroscopy (MH⁺) 382.

Example A33 Synthesis of N-(4-azidophenyl)alanine iso-butyl ester

[3118] Following General Procedure AA above and using 4-azidoaniline(Aldrich) and iso-butyl pyruvate (prepared by following GeneralProcedure AO above), the title compound was prepared as an oil. Thereaction was monitored by tlc on silica gel (Rf=0.3 in 25%EtOAc/hexanes) and purification was by preparative plate chromatography(silica gel using 25% EtOAc/hexanes as the eluant).

[3119] NMR data was as follows:

[3120]¹H-nmr (CDCl₃): δ=7.3 (d, 2H), 6.8 (d, 2H), 4.30 (bs, 1H), 4.08(q, 1H), 1.94 (sept, 1H), 1.47 (d, 3H), 0.91 (d, 6H).

[3121]¹³C-nmr (CDCl₃): δ=174.5, 148.7, 131.5, 130.3, 121.3, 114.9,113.6, 72.0, 52.4, 28.3, 19.5, 19.3.

[3122] C₁₃H₁₈N₄O₂ (MW=262.31); mass spectroscopy (MH⁺) 263.

Example A34 Synthesis of N-[(4-phenylcarbonyl)phenyl]alanine iso-butylester

[3123] Following General Procedure AA above and using4′-aminobenzophenone (Aldrich) and iso-butyl pyruvate (prepared byfollowing General Procedure AO above), the title compound was preparedas an oil. The reaction was monitored by tlc on silica gel (Rf=0.4 in25% EtOAc/hexanes) and purification was by preparative platechromatography (silica gel using 25% EtOAc/hexanes as the eluant).

[3124] NMR data was as follows:

[3125]¹H-nmr (CDCl₃): δ=7.7 (d, 2H), 7.1 (m, 5H), 6.9 (d, 2H), 4.30 (bs,1H), 4.08 (q, 1H), 1.94 (sept, 1H), 1.47 (d, 3H), 0.91 (d, 6H).

[3126]¹³C-nmr (CDCl₃): δ=199, 178.5, 149.7, 131.5, 130.3, 126, 121.3,114.9, 113.6, 72.0, 52.4, 28.3, 19.5, 19.3.

[3127] C₂₀H₂₃NO₃ (MW=325.41); mass spectroscopy (MH⁺) 326.

Example A35 Synthesis of N-(3,5-difluorophenyl)alanine iso-butyl ester

[3128] Following General Procedure AH above and usingN-(3,5-difluorophenyl)alanine (from Example AC above) and iso-butanol,the title compound was prepared as an oil. The reaction was monitored bytlc on silica gel (Rf=0.9 in 3% methanol/methylene chloride) andpurification was by preparative plate chromatography (silica gel using3% methanol/methylene chloride as the eluant).

[3129] NMR data was as follows:

[3130]¹H-nmr (CDCl₃): δ=6.1 (m, 3H), 4.5 (bs, 1H), 4.1 (d, 1H), 3.95 (m,2H), 2.0 (m, 1H), 1.5 (d, J=7 Hz, 3H), 0.95(d, J=6 Hz, 6H).

[3131]¹³C-nmr (CDCl₃): δ=174.44, 166.40, 166.19, 163.16, 162.95, 149.43,96.73, 96.60, 96.48, 96.35, 94.06, 93.72, 93.37, 72.03, 52.30, 28.29,19.47, 19.23.

[3132] C₁₃H₁₇F₂NO₂ (MW=290.2); mass spectroscopy (MH⁺) 291.

Example A36 Synthesis of N-(3,4-dichlorophenyl)alanine0-acylacetamidoxime ester

[3133] Following General Procedure AK above and usingN-(3,4-dichlorophenyl)alanine (from Example AB above) and acetamideoxime (prepared according to the procedures described in J. Org. Chem.,46, 3953 (1981)), the title compound was prepared as a semisolid. Thereaction was monitored by tlc on silica gel (Rf=0.4 in ethyl acetate)and purification was by preparative plate chromatography (silica gelusing ethyl acetate as the eluant).

[3134] NMR data was as follows:

[3135]¹H-nmr (DMSO-d₆): δ=7.27 (d, 1H), 6.81 (s, 1H) 6.4 (broad s, 2H),6.62 (d, 1H), 6.45 (d, 1H), 4.22 (m, 1H), 1.74 (s, 3H), 1.40 (d, 3H).

[3136] C₁₁H₁₃Cl₂N₃O₂ (MW=290.15); mass spectroscopy (MH⁺) 291.

Example A37 Synthesis of N-(3,4-dichlorophenyl)alanine pyrrolyl amide

[3137] Following General Procedure AL above and usingN-(3,4-dichlorophenyl)alanine (from Example AB above) and pyrrole(Aldrich), the title compound was prepared as an oil. The reaction wasmonitored by tlc on silica gel (Rf=0.28 in 10% ethyl acetate/hexanes)and purification was by preparative plate chromatography (silica gelusing 10% ethyl acetate/hexanes as the eluant).

[3138] NMR data was as follows:

[3139]¹H-nmr (CDCl₃): δ=7.36 (d, J=2.2, 2H); 7.20 (d, J=8.7, 1H); 6.71(d, J=2.7, 1H); 6.5 (m, 1H); 6.38 (t, J=2.4, 2H); 4.8 (m, 1H); 4.57 (d,J=8.7, 1H); 1.59 (d, J=6.8, 3H).

[3140]¹³C-nmr (CDCl₃): δ=171.9, 146.1, 133.6, 131.5, 121.9, 119.6,115.4, 114.7, 113.8, 51.8, 20.2.

[3141] C₁₃H₁₂Cl₂N₂O (MW=283); mass spectroscopy (MH⁺) 284.

Example A38 Synthesis of N-(3,4-dichlorophenyl)alanine0-acylbutyramideoxime ester

[3142] Following General Procedure AI above and usingN-(3,4-dichlorophenyl)alanine 2,4,6-trichlorophenyl ester (prepared fromN-(3,4-dichlorophenyl)alanine methyl ester (from Example A9) usingessentially the same procedure as described in Example AE above) andbutyramide oxime (prepared according to the procedures described in J.Org. Chem., 46, 3953 (1981)), the title compound was prepared as asemisolid. The reaction was monitored by tlc on silica gel (Rf=0.25 in50% ethyl acetate/hexanes) and purification was by preparative platechromatography (silica gel using 50% ethyl acetate/hexanes as theeluant).

[3143] NMR data was as follows:

[3144]¹H-nmr (d₆-DMSO): δ=7.27 (d, 1H), 6.83 (s, 1H) 6.38 (broad s, 2H),6.61 (d, 1H), 6.46 (d, 1H), 4.25 (m, 1H), 2.02 (t, 2H), 1.55 (m, 2H),1.40 (d, 3H), 0.88 (t, 3H).

[3145] C₁₃H₁₇Cl₂N₃O₂ (MW=318.20); mass spectroscopy (MH⁺) 319.

Example A39 Synthesis of 2-[N-(naphth-2-yl)amino]butanoic acid ethylester

[3146] Following General Procedure AJ above and using 2-aminonaphthalene(Aldrich) and ethyl 2-bromobutyrate (Aldrich), the title compound wasprepared as a solid, m.p. 81-83° C. The reaction was monitored by silicagel tlc (Rf=0.5 in CHCl₃). Purification was by chromatography (silicagel using chloroform as the eluant).

[3147] NMR data was as follows: ¹H-nmr (d⁶-DMSO): δ=7.63 (m, 2H), 7.54(d, 1H), 7.31(t, 1H), 7.12 (t, 1H), 7.03 (d, 1H), 6.62 (s, 1H), 6.32 (d,1H), 4.15 (m, 3H), 1.42 (d, 3H), 1.19 (t, 3H).

[3148] C₁₆H₁₉NO₂ (MW=257.34); mass spectroscopy (MH⁺) 258.

Example A40 Synthesis of N-(2-naphthyl)alanine iso-butyl ester

[3149] Following General Procedure AA above and using 2-aminonaphthalene(Aldrich) and iso-butyl pyruvate (prepared by following GeneralProcedure AO above), the title compound was prepared as an oil.Purification was by preparative plate chromatography (silica gel using25% EtOAc/hexanes as the eluant).

[3150] NMR data was as follows:

[3151]¹H-nmr (CDCl₃): δ=7.65 (m, 3H), 7.38 (t, 1H, J=6.9 Hz), 7.23 (t,1H, J=6.9 Hz), 6.93 (m, 1H), 6.81 (d, 1H, J=2.3 Hz), 4.31 (q, 1H, J=6.9Hz), 3.95 J=6.7 Hz, J=1.6 Hz), 1.96 (sept, 1H, J=6.7 Hz), 1.57 (d, 3H,J=6.9 Hz), 0.93 (dd, 6H, J=6.7 Hz, J=1.6 Hz).

[3152]¹³C-nmr (CDCl₃) δ=174.6, 144.2, 134.9, 129.1, 127.8, 127.6, 126.3,126.0, 122.3, 118.1, 105.3, 71.2, 52.0, 27.7, 18.9, 18.8.

Example A41 Synthesis of N-(2-methylquinolin-6-yl)alanine iso-butylester

[3153] Following General Procedure AA above and using6-amino-2-methylquinoline (Lancaster) and iso-butyl pyruvate (preparedby following General Procedure AO above), the title compound wasprepared. The reaction was monitored by silica gel tlc (Rf=0.44 in 50%EtOAc/hexanes). Purification was by flash chromatography (silica gelusing 50% EtOAc/hexanes as the eluant).

[3154] NMR data was as follows:

[3155]¹H-nmr (CDCl₃): δ=7.90 (m. 2H), 7.10 (m, 2H), 6.66 (d, 1H, J=2.6),4.50 (bd, 1H), 4.24 (m, 1H), 3.91 (d, 2H, J=6.6 Hz), 2.64 (s, 3H), 1.91(sept 1H, J=6.7 Hz), 1.52 (d, 3H, J=6.9 Hz), 0.87 (d, 6H, J=6.7 Hz).

[3156]¹³C-nmr (CDCl₃) δ=175.0, 155.4, 144.6, 143.4, 134.9, 130.2, 128.4,122.8, 121.8, 104.9, 71.8, 52.7, 28.3, 25.4, 19.5, 19.4.

[3157] C₁₇H₂₂Cl₂N₂O₂ (MW=286.38); mass spectroscopy (MH⁺) 287.

Example A42 Synthesis of N-(3,4-methylenedioxyphenyl)alanine iso-butylester

[3158] Following reductive amination General Procedure AA above andusing 3,4-methylenedioxyaniline (Aldrich) and methyl pyruvate (Aldrich),N-(3,4-methylenedioxyphenyl)alanine methyl ester was prepared. Themethyl ester was then transesterified following General Procedure AQabove and using iso-butanol to provide the title compound as an oil. Thereaction was monitored by silica gel tlc (Rf=0.61 in 25% EtOAc/hexanes).Purification was by preparative plate chromatography with silica gelusing 25% EtOAc/hexanes as the eluant.

[3159] NMR data was as follows:

[3160]¹H-nmr (CDCl₃): δ=6.63 (d, 1H, 8.3Hz), 6.25 (d, 1H, J=2.3 Hz),6.04 (dd, 1H, J=8.3 Hz, J=2.3 Hz), 5.83 (s, 2H), 3.96 (m, 4H), 1.92(sept, 1H, 3J =6.7 Hz), 1.44 (d, 3H, J=6.9 Hz), 0.90 (d, 6H, J=6.6 Hz).

[3161]¹³C-nmr (CDCl₃): δ=175.4, 148.9, 142.9, 140.8, 109.2, 105.8,101.2, 97.4, 71.6, 53.6, 28.3, 19.6, 19.5.

[3162] C₁₄H₁₉NO₄ (MW=265.31); mass spectroscopy (M⁺) 265.

Example A43 Synthesis of N-(3,4-ethylenedioxyphenyl)alanine iso-butylester

[3163] Following reductive amination General Procedure AA above andusing 1,4-benzodioxa-6amine (Aldrich) and methyl pyruvate (Aldrich),N-(3,4-ethylenedioxyphenyl)alanine methyl ester was prepared. The methylester was then transesterified following General Procedure AQ aboveusing iso-butanol to provide the title compound. Purification was bypreparative plate chromatography.

[3164] NMR data was as follows:

[3165]¹H-nmr (CDCl₃): δ=0.91 (d, δ=7 Hz, 6H), 1.42 (d, J=7 Hz, 3H),1.8-2 (m, 1H), 3.8-3.95 (m, 3H), 4.0-4.1 (m, 1H), 4.15-4.25 (m, 4H),6.12-6.2 (m, 2H), 6.65-6.75 (m, 1H).

[3166]¹³C-nmr (CDCl₃): δ=19.55, 19.56, 19.67, 28.3, 53.4, 64.7, 65.3,71.7, 103.1, 108.0, 118.3, 142.1, 144.6, 175.4.

[3167] C₁₅H₂₁NO₄ (MW=279.34); mass spectroscopy (MH⁺) 280.

Example A44 Synthesis of N-(2-naphthyl)alanine methyl ester

[3168] Following reductive amination General Procedure AA above andusing 2-aminonaphthalene (Aldrich) and methyl pyruvate (Aldrich), thetitle compound was prepared. The reaction was monitored by silica geltlc (Rf=0.50 in 25% EtOAc/hexanes). Purification was by flashchromatography with silica gel using 25% EtOAc/hexanes as the eluant.

[3169] NMR data was as follows:

[3170]¹H-nmr (CDCl₃): δ=7.65 (m, 3H), 7.48 (m, 1H), 7.25 (m, 1H), 6.91(m, 1H), 6.79 (m, 1H), 4.31 (m, 2H), 3.76 (s, 3H), 1.55 (d, 3H).

[3171]¹³C-nmr (CDCl₃): δ=175.66, 144.78, 135.55, 129.78, 128.47, 128.22,126.96, 126.67, 123.01, 118.66, 105.88, 52.95, 52.51, 19.45.

[3172] C₁₄H₁₅NO₂ (MW=229.28); mass spectroscopy (MH⁺) 229.

Example A45 Synthesis of N-(benzothiazol-6-yl)alanine ethyl ester

[3173] To a solution of 6-aminobenzothiazole (Lancaster) indichloromethane was added 1.2 equivalents of pyridine, followed by 1.5equivalents of trifluoroacetic anhydride. The reaction was stirred atroom temperature for 3 hours and then washed with 5% citric acid, driedover MgSO₄, and stripped free of solvent on a rotary evaporator to yield6-trifluoroacetamidothiazole. This material was dissolved in THF andthen added to a suspension of KH in THF at 0° C. A catalytic amount of18-crown-6 was added, followed by ethyl 2-bromopropionate (Aldrich). Thereaction was held at room temperature for 1 hour, and then heated toreflux for 24 hours, and then cooled to room temperature. The reactionmixture was stripped free of solvent on a rotary evaporator and theresulting residue was dissolved in ether. This solution was washed withwater, saturated aqueous NaCl, and dried over MgSO₄. The solution wasstripped free of solvent on a rotary evaporator and the title compoundwas obtained by chromatography of the residue using 5%methanol/dichloromethane (Rf=0.59) as the eluant.

[3174] NMR data was as follows:

[3175]¹H-nmr (CDCl₃): δ=8.69 (s, 1H), 7.90 (d, 1H, J=8.8 Hz), 7.04 (d,1H, J=2.3 Hz), 6.84 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 4.41 (bd, 1H, J=7.5Hz), 4.20 (m, 3H), 1.53 (d, 3H, J=6.9 Hz), 1.27 (t, 3H, J=7.1 Hz).

[3176]¹³C-nmr (CDCl₃): δ=174.9, 150.2, 147.1, 145.6, 136.3, 124.6,115.7, 103.5, 61.9, 52.9, 19.4, 14.8.

[3177] C₁₂H₁₄N₂O₂S (MW=250.32); mass spectroscopy (MH⁺) 251.

Example A46 Synthesis of N-(indol-5-yl)alanine iso-butyl ester (Sisomer)

[3178] Following General Procedure AM and using 5-aminoindole (Aldrich)and iso-butyl R-(+)-lactate (Aldrich), the title compound was preparedas an oil. The reaction was monitored by silica gel tlc (Rf=0.46 in 33%EtOAc/hexanes). Purification was by preparative plate chromatographywith silica gel using 33% EtOAc/hexanes as the eluant.

[3179] NMR data was as follows:

[3180]¹H-nmr (CDCl₃): δ=8.11 (bs, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.98 (d,J=2.8 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.61 (m, 1H), 6.32 (m, 1H), 4.18(q, J=6.9 H 1H), 3.95 (bs, 1H), 3.87 (d, J=6.7 Hz, 2H), 1.89 (hept,J=6.7 Hz, 1H), 1.48 (d, J=6.96 Hz, 3H), 0.86 (dd, J=6.7 Hz, J=1.6 Hz,6H).

[3181]¹³C-nmr (CDCl₃): δ=176.15, 141.06, 131.28, 129.24, 125.34, 113.34,112.53, 104.21, 102.17, 71.65, 54.28, 28.36, 19.87, 19.62.

[3182] C₁₅H₂₀N₂O₂ (MW=260.34); mass spectroscopy (MH⁺) 261.

Example A47 Synthesis of N-(naphth-2-yl)alanine 0-acylacetamidoximeester

[3183] Following General Procedure AI above using N-(naphth-2-yl)alanine2,4,6-trichlorophenyl ester (from Example AE above) and acetamide oxime(prepared according to the procedures described in J. Org. Chem., 46,3953 (1981)), the title compound was prepared as a semisolid. Thereaction was monitored by tlc on silica gel (Rf=0.4 in ethyl acetate)and purification was by preparative plate chromatography (silica gelusing ethyl acetate as the eluant).

[3184] NMR data was as follows:

[3185]¹H-nmr (d⁶-DMSO): δ=7.64 (t, 2H), 7.54 (d, 1H), 7.32 (t, 1H), 7.13(t, 1H) 7.04 (d, 1H), 6.78 (s, 1H) 6.42 (broad s, 2H), 6.32 (d, 1H),4.33 (m, 1H), 1.72 (s, 3H), 1.46 (d, 3H).

[3186] C₁₅H₁₇N₃O₂ (MW=271.32); mass spectroscopy: 271.

Example A48 Synthesis of N-(2-naphthyl)alanine ethyl ester

[3187] Following reductive amination General Procedure AA above andusing 2-aminonaphthalene (Aldrich) and ethyl pyruvate (Aldrich), thetitle compound was prepared as a solid having a melting point of 52-56°C. The reaction was monitored by silica gel tlc (Rf=0.50 in 25%EtOAc/hexanes). Purification was by flash chromatography with silica gelusing 25% EtOAc/hexanes as the eluant.

[3188] NMR data was as follows:

[3189]¹H-nmr (CDCl₃): δ=7.65 (m, 3H), 7.48 (m, 1H), 7.25 (m, 1H), 6.91(m, 1H), 6.79 (m, 1H), 4.31 (m, 2H), 3.76 (s, 3H), 1.55 (d, 3H).

[3190]¹³C-nmr (CDCl₃): δ=175.66, 144.78, 135.55, 129.78, 128.47, 128,22,126.96, 126.67, 123.01, 118.66, 105.88, 52.95, 52.51, 19.45.

[3191] C₁₄H₁₅NO₂ (MW=229.28); mass spectroscopy (MH⁺) 229.

Example A49 Synthesis of N-(3,4-dichlorophenyl)alanineO-acylpropionamidoxime ester

[3192] Following General Procedure AI above usingN-(3,4-dichlorophenyl)alanine 2,4,6-trichlorophenyl ester (prepared fromN-(3,4-dichlorophenyl)alanine methyl ester (from Example A9) usingessentially the same procedure as described in Example AE above) andpropionamide oxime (prepared according to the procedures described in J.Org. Chem., 46, 3953 (1981)), the title compound was prepared as asemisolid. The reaction was monitored by tlc on silica gel (Rf=0.2 in50% ethyl acetatelhexane) and purification was by preparative platechromatography (silica gel using 50% ethyl acetate/hexane as theeluant).

[3193] NMR data was as follows:

[3194]¹H-nmr (d⁶-DMSO): δ=7.27 (d, 1H), 6.83 (s, 1H), 6.64 (d, 1H), 6.47(d, 1H), 6.38 (broad s, 2H), 4.24 (m, 1H), 2.07 (q, 2H), 1.41 (d, 3H).

[3195] C₁₂H₁₅Cl₂N₃O₂ (MW=304.17); mass spectroscopy (MH⁺) 305.

Example A50 Synthesis of N-(4-ethoxycarbonylphenyl)alanine iso-butylester (S isomer)

[3196] Following General Procedure AM and using ethyl 4-aminobenzoate(Aldrich) and iso-butyl R-(+)-lactate (Aldrich), the title compound wasprepared as an oil. The reaction was monitored by silica gel tlc(Rf=0.21 in 10% EtOAc/hexanes). Purification was by preparative platethin layer chromatography using 25% EtOAc/hexanes as the eluant.

[3197] NMR data was as follows:

[3198]¹H-nmr (CDCl₃): δ=7.82 (d, J=8.73 Hz, 2H), 6.51 (d, J=8.79 Hz,2H), 4.81 (d, J=7.82 Hz, 1H), 4.25 (q, J=7.14 Hz, 2H), 4.15 (quint,J=7.40 Hz, 1H), 3.87 (m, 2H), 1.87 (sept, J=6.70 Hz, 1H), 1.43 (d,J=6.95 Hz, 3H), 1.30 (t, J=7.14 Hz, 3H), 0.84 (d, J=6.71 Hz, 6H).

[3199]¹³C-nmr (CDCl₃): δ=174.5, 167.3, 151.0, 132.0, 119.9, 112.5, 71.9,60.8, 51.9, 28.2, 19.5, 19.2, 15.0.

[3200] C₁₆H₂₃NO₄ (MW=293.37); mass spectroscopy (MH⁺) 294.

Example A51 Synthesis of N-[3,5-di(trifluoromethyl)phenyl]alanineiso-butyl ester (S isomer)

[3201] Following General Procedure AM and using3,5-di(trifluoromethyl)aniline (Aldrich) and iso-butyl R-(+)-lactate(Aldrich), the title compound was prepared as an oil. The reaction wasmonitored by silica gel tlc (Rf=0.38 in 10% EtOAc/hexanes). Purificationwas by preparative plate thin layer chromatography using 10%EtOAc/hexanes as the eluant.

[3202] NMR data was as follows:

[3203]¹H-nmr (CDCl₃): δ=7.13 (s, 1H), 6.91 (s, 2H), 4.97 (d, J=8.24 Hz,1H), 4.18 (m, 1H), 3.93 (d, J=6.59 Hz, 2H), 1.93 (sept, J=6.71 Hz, 1H),1.49 (d, J=7.02 Hz, 3H), 0.89 (d, J=6.59 Hz, 6H).

[3204]¹³C-nmr (CDCl₃): δ=174.4, 147.9, 133.6, 133.2, 132.7, 132.3,129.4, 125.8, 122.2, 118.6, 112.81, 112.76, 111.42, 111.37, 111.32,111.27, 111.22, 72.2, 52.0, 32.1, 28.24, 28.17, 23.2, 19.5, 19.3, 19.2,18.9, 14.6.

[3205] C₁₅H₁₇F₆NO₂ (MW=357.30); mass spectroscopy (MH⁺) 358.

Example A52 Synthesis of N-(3,5-dimethoxyphenyl)alanine iso-butyl ester

[3206] N-(3,5-dimethoxyphenyl)alanine (crude, 454 mg) (preparedaccording to the procedure described in U.S. Pat. No. 3,598,859 using3,5-dimethoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich)) wastreated in dry iso-butanol (10 mL) with 0.1 mL of chlorotrimethylsilaneand the reaction mixture refluxed overnight. The excess alcohol wasremoved at reduced pressure and the residue dissolved in ethyl acetate.The ethyl acetate solution was washed with saturated aqueous NaHCO₃,dried with Na₂SO₄ and the solvent removed to provide the title compound.The reaction was monitored by silica gel tlc (Rf=0.3 in 20%EtOAc/hexanes). Purification was by preparative thin layerchromatography using 20% EtOAc/hexanes as the eluant.

[3207] NMR data was as follows:

[3208]¹H-nmr (CDCl₃): δ=0.9 (d, J=7, 6H), 1.47 (d, J=7, 3H), 1.9-2.0 (m,1H), 3.7 (s, 6H), 3.85-4.0 (m, 2H), 4.1-4.2 (m, 1H), 4.3 (brs, 1H), 5.8(s, 1H) 5.9 (s, 1H).

[3209]¹³C-nmr (CDCl₃): δ=19.49, 19.52, 19.54, 28.3, 52.5, 55.6, 71.7,91.1, 92.7, 149.2, 162.3, 175.2.

[3210] C₁₅H₂₃NO₄ (MW=281.35).

Example A53 Synthesis of N-(2-napthyl)alanine O-acylpropionamidoximeester

[3211] Following General Procedure AS and using N-(2-naphthyl)alanine2,4,5-trichlorophenyl ester (from Example AE above) and propionamideoxime (prepared according to the procedures described in J. Org. Chem.,46, 3953 (1981)), the title compound was prepared. The reaction wasmonitored by silica gel tlc (Rf=0.5 in EtOAc). Purification was bysilica gel chromatography using 1:1 EtOAc/hexanes as the eluant.

[3212] NMR data was as follows:

[3213]¹H-nmr (DMSO-d₆): δ=1.03 (t, 3H), 1.45 (d, 3H).

[3214] C₁₆H₁₉N₃O₂ (MW=285.35); mass spectroscopy (M⁺) 285.

Example A54 Synthesis of N-(2-napthyl)alanine 0-acylbutyramidoxime ester

[3215] Following General Procedure AS and using N-(2-naphthyl)alanine2,4,5-trichlorophenyl ester (from Example AE above) and butyramide oxime(prepared according to the procedures described in J. Org. Chem., 46,3953 (1981)), the title compound was prepared as an oil. The reactionwas monitored by silica gel tic (Rf=0.6 in EtOAc). Purification was bysilica gel chromatography using 1:1 EtOAc/hexanes as the eluant.

[3216] NMR data was as follows:

[3217]¹H-nmr (DMSO-d₆): δ=0.86 (t, 3H), 1.46 (d, 3H).

[3218] C₁₇H₂₁N₃O₂ (MW=299.37); mass spectroscopy (MH⁺) 299.

Example A55 Synthesis of N-(2-napthyl)alanine O-acylisovaleramidoximeester

[3219] Following General Procedure AS and using N-(2-naphthyl)alanine2,4,5-trichlorophenyl ester (from Example AE above) and isovaleramideoxime (prepared according to the procedures described in J. Org. Chem.,46, 3953 (1981)), the title compound was prepared as an oil. Thereaction was monitored by silica gel tlc (Rf=0.3 in 1:1 EtOAc/hexanes).Purification was by silica gel chromatography using 1:1 EtOAc/hexanes asthe eluant.

[3220] NMR data was as follows:

[3221]¹H-nmr (DMSO-d₆): δ=0.86 (t, 3H), 1.45 (d, 3H).

[3222] C₁₈H₂₃N₃O₂ (MW=313.40); mass spectroscopy (MH⁺) 313.

Example A56 Synthesis of N-(2-napthyl)alanine O-acylbenzamidoxime ester

[3223] Following General Procedure AS and using N-(2-naphthyl)alanine2,4,5-trichlorophenyl ester (from Example AE above) and benzamide oxime(prepared according to the procedures described in J. Org. Chem., 46,3953 (1981)), the title compound was prepared as an oil. The reactionwas monitored by silica gel tlc (Rf=0.3 in 1:1 EtOAc/hexanes).Purification was by silica gel chromatography using 1:1 EtOAc/hexanes asthe eluant.

[3224] NMR data was as follows:

[3225]¹H-nmr (DMSO-d₆): δ=4.42 (m, 1H), 1.53 (d, 3H).

[3226] C₂₀H₁₉N₃O₂ (MW=333.39); mass spectroscopy (MH⁺) 333.

Example A57 Synthesis of N-(2-napthyl)alanineO-acylcyclopropanecarboxamidoxime ester

[3227] Following General Procedure AS and using N-(2-naphthyl)alanine2,4,5-trichlorophenyl ester (from Example AE above) andcyclopropanecarboxamide oxime (prepared according to the proceduresdescribed in J. Org. Chem., 46, 3953 (1981)), the title compound wasprepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.3in 1:1 EtOAc/hexanes). Purification was by silica gel chromatographyusing 1:1 EtOAc/hexanes as the eluant.

[3228] NMR data was as follows:

[3229]¹H-nmr (DMSO-d₆): δ=0.85 (m, 4H), 1.43 (d, 3H).

[3230] C₁₇H₁₉N₃O₂ (MW=297.36); mass spectroscopy (MH⁺) 297.

Example A58 Synthesis of N-(2-napthyl)alanineO-acylcyclopropylacetamidoxime ester

[3231] Following General Procedure AS and using N-(2-naphthyl)alanine2,4,5-trichlorophenyl ester (from Example AE above) andcyclopropylacetamide oxime (prepared according to the proceduresdescribed in J. Org. Chem., 46, 3953 (1981)), the title compound wasprepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.3in 1:1 EtOAc/hexanes). Purification was by silica gel chromatographyusing 1:1 EtOAc/hexanes as the eluant.

[3232] NMR data was as follows:

[3233]¹H-nmr (DMSO-d₆): δ=1.43 (d, 3H), 1.91 (d, 2H).

[3234] C₁₈H₂₁N₃O₂ (MW=311.39); mass spectroscopy (MH⁺) 311.

Example A59 Synthesis of N-(2-napthyl)alanineO-acylcyclopentanecarboxamidoxime ester

[3235] Following General Procedure AS and using N-(2-naphthyl)alanine2,4,5-trichlorophenyl ester (from Example AE above) andcyclopentanecarboxamide oxime (prepared according to the proceduresdescribed in J. Org. Chem., 46, 3953 (1981)), the title compound wasprepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.3in 1:1 EtOAc/hexanes). Purification was by silica gel chromatographyusing 1:1 EtOAc/hexanes as the eluant.

[3236] NMR data was as follows:

[3237]¹H-nmr (DMSO-d₆): δ=1.43 (d, 3H), 2.43 (m, 1H).

[3238] C₁₇H₁₉N₃O₂ (MW=297.36).

General Procedure BA Coupling of R¹C(X′)(X″)C(O)Cl with H₂NCH(R²)C(O)XR³

[3239] To a stirred solution of (D,L)-alanine iso-butyl esterhydrochloride (from Example BB below) (4.6 mmol) in 5 mL of pyridine wasadded 4.6 mmol of an acid chloride. Precipitation occurred immediately.The mixture was stirred for 3.5 h, diluted with 100 mL of diethyl ether,washed with 10% HCl three times, brine once, 20% potassium carbonateonce and brine once. The solution was dried over magnesium sulfate,filtered, and evaporated at reduced pressure to yield the product. Otheramino acid esters may also be employed in this procedure.

General Procedure BB Coupling of R¹C(X′)(X″)C(O)OH with H₂NCH(R²)C(O)XR³

[3240] A solution of the acid (3.3 mmol) and CDI in 20 mL THF wasstirred for 2 h. L-alanine iso-butyl ester hydrochloride (from ExampleBB below) (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) oftriethylamine. The reaction mixture was stirred overnight. The reactionmixture was diluted with 100 mL of diethyl ether, washed with 10% HClthree times, brine once, 20% potassium carbonate once and brine once.The solution was dried over magnesium sulfate, filtered, and evaporatedat reduced pressure to yield the product. Other amino acid esters mayalso be employed in this procedure.

General Procedure BC

[3241] Esterification of R¹C(X′)(X″)C(O)NHCH(R²)C(O)OH With HOR³

[3242] To a stirred solution of phenylacetylvaline (1.6470 g, 7.0 mmol)in 20 mL THF was added CDI (1.05 g, 6.5 mmol) and the mixture wasstirred for 1.5 h. 2-Methylbutanol (0.53 g, 6 mmol) was added themixture, followed by addition of NaH (0.16 g, 6.5 mmol). Bubblingoccurred immediately. The reaction mixture was stirred overnight. Thereaction mixture was diluted with 100 mL of diethyl ether, washed with10% HCl three times, brine once, 20% potassium carbonate once and brineonce. The solution was dried over magnesium sulfate, filtered, andevaporated at reduced pressure to yield the product. Other N-acyl aminoacids and alcohols may also be employed in this procedure.

General Procedure BD Ester Hydrolysis to the Free Acid

[3243] Ester hydrolysis to the free acid was conducted by conventionalmethods. Below are two examples of such conventional de-esterificationmethods.

[3244] To the ester in a 1:1 mixture of CH₃OH/H₂O was added 2-5equivalents of K₂CO₃. The mixture was heated to about 50° C. for about0.5 to 1.5 hours until tlc showed complete reaction. The reaction wascooled to room temperature and the methanol was removed at reducedpressure. The pH of the remaining aqueous solution was adjusted to about2, and ethyl acetate was added to extract the product. The organic phasewas then washed with saturated aqueous NaCl and dried over MgSO₄. Thesolution was stripped free of solvent at reduced pressure to yield theproduct.

[3245] The amino acid ester was dissolved in dioxane/water (4:1) towhich was added LiOH (˜2 eq.) that was dissolved in water such that thetotal solvent after addition was about 2:1 dioxane:water. The reactionmixture was stirred until reaction completion and the dioxane wasremoved under reduced pressure. The residue was diluted with EtOAc, thelayers were separated and the aqueous layer acidified to pH 2. Theaqueous layer was back extracted with EtOAc, the combined organics weredried over Na₂SO₄ and the solvent was removed under reduced pressureafter filtration. The residue was purified by conventional methods(e.g., recrystallization).

[3246] The following exemplifies this later example. The methyl ester of3-NO₂ phenylacetyl alanine 9.27 g (0.0348 mols) was dissolved in 60 mLdioxane and 15 mL of H₂O and adding LiOH (3.06 g, 0.0731 mol) that hasbeen dissolved in 15 mL of H₂. After stirring for 4 hours, the dioxanewas removed under reduced pressure and the residue diluted with EtOAc,the layers were separated and the aqueous layer acidified to pH 2. Theaqueous layer was back extracted with EtOAc (4×100 mL), the combinedorganics were dried over Na₂SO₄ and the solvent was removed underreduced pressure after filtration. The residue was recrystallized fromEtOAc/isooctane giving 7.5 g (85%) of 3-nitrophenylacetyl alanine.C₁₁H₁₂N₂O₅ requires C=52.38, H=4.80, and N=11.11. Analysis foundC=52.54, H=4.85, and N=11.08. [α]₂₃=−29.9 @ 589 nm.

General Procedure BE Low Temperature BOP Coupling of Acid and Alcohol

[3247] A solution of methylene chloride containing the carboxylic acid(100M %) and N-methyl morpholine (150 M %) was cooled to -20° C. undernitrogen. BOP (105 M %) was added in one portion and the reactionmixture was maintained at −20° C. for 15 minutes. The correspondingalcohol (120 M %) was added and the reaction mixture was allowed to warmto room temperature and stirred for 12 hours. The reaction mixture wasthen poured into water and extracted with ethyl acetate (3×). Thecombined ethyl acetate portions were backwashed with saturated aqueouscitric acid (2×), saturated aqueous sodium bicarbonate (2×), brine (1×),dried over anhydrous magnesium sulfate or sodium sulfate and the solventremoved under reduced pressure to yield the crude product.

General Procedure BF

[3248] EDC Coupling of Acid and Amine

[3249] The acid derivative was dissolved in methylene chloride. Theamine (1 eq.), N-methylmorpholine (5 eq.), and hydroxybenzotriazolemonohydrate (1.2 eq.) were added in sequence. The reaction was cooled toabout 0° C. and then 1.2 eq. of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added.The solution was allowed to stir overnight and come to room temperatureunder N. pressure. The reaction mix was worked up by washing thesolution with saturated, aqueous NACO₂CO₃, 0.1M citric acid, and brinebefore drying with NA₂SO₄ and removal of solvents to yield crudeproduct. Pure products were obtained by flash chromatography in anappropriate solvent.

General Procedure BG EDC Coupling of Acid and Amine

[3250] A round bottom flask was charged with carboxylic acid (1.0 eq.),hydroxy-benzotriazole hydrate (1.1 eq.) and amine (1.0 eq.) in THF undernitrogen atmosphere. An appropriate amount (1.1 eq. for free amines and2.2 eq. for hydrochloride amine salts) of base, such as Hunig's base wasadded to the well stirred mixture followed by EDC (1.1 eq.). Afterstirring from 4 to 17 hours at room temperature the solvent was removedat reduced pressure, the residue taken up in EtOAc (or similarsolvent)/water. The organic layer was washed with saturated aqueoussodium bicarbonate solution, 1N HCl, brine and dried over anhydroussodium sulfate. In some cases, the isolated product was analyticallypure at this stage while, in other cases, purification viachromatography and/or recrystallization was required prior to biologicalevaluation.

General Procedure BH Coupling of R¹C(X′)(X″)C(O)Cl with H₂NCH(R²)C(O)XR³

[3251] An excess of oxalyl chloride in dichloromethane was added to theacid derivative together with one drop of DMF. The resulting mixture wasstirred for about 2 hours or until bubbling ceases. The solvent was thenremoved under reduced pressure and rediluted with dry methylenechloride. To the resulting solution was added about 1.1 eq. of theappropriate amino acid ester and triethylamine (1.1 eq. in methylenechloride). The system was stirred at room temperature for 2 hours andthen the solvent was removed under reduced pressure. The residue wasdissolved in ethyl acetate, washed with 1N HCl followed by 1N NaOH. Theorganic layer was dried over anhydrous soldium sulfate, filtered and thesolvent removed under reduced pressure to provide for the desiredproduct.

General Procedure BI P-EPC coupling

[3252] P-EPC coupling employs an amino acid ester and a substitutedacetic acid compound. The acetic acid derivative is well known in theart and is typically commercially available. The amino acid ester isprepared by conventional methods from the known and typicallycommercially available N-BOC amino acid as described in GeneralProcedure BJ below.

[3253] Specifically, the appropriate amino ester free base (0.0346mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in2.0 mL CHCl₃ (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) andthe reaction was mixed for 4 days at 23° C. The reaction was filteredthrough a plug of cotton, rinsed with 2.0 mL of CHCl₃ and the filtrateevaporated under a stream of nitrogen. The purity of each sample wasdetermined by ¹H NMR and ranged from 50% to >95%. Between 8.0 and 15.0mg of final product was obtained from each reaction and was testedwithout additional purification.

General Procedure BJ Synthesis of Amino Acid Esters From theCorresponding N-BOC Amino Acid

[3254] A. Esterification of the Acid.

[3255] The N-BOC amino acid was dissolved in dioxane and treated with anexcess of alcohol (˜1.5 eq.) and catalytic DMAP (100 mg) at 0° C.Stirring was continued until reaction completion whereupon the productwas recovered by conventional methods.

[3256] B. Removal of N-BOC Group.

[3257] The N-BOC protected amino acid was dissolved in methylenechloride (0.05M) and treated with 10 eq. of TFA at room temperatureunder a nitrogen atmosphere. The reaction was monitored by tlc untilstarting material was consumed usually within 1-5 hours. An additional10 eq. of TFA was added to the reaction if the starting material wasstill present after 5 hours. The reaction was carefully neutralized withNa₂CO₃, separated, the organic layer washed with brine and dried overanhydrous Na₂SO₄. The crude amine was then used without purification.

[3258] Specific exemplification of these procedures are as follows:

[3259] 1. Racemic (+/−)-N-BOC-α-amino butyric acid (Aldrich) (9.29 g,0.0457 mol) was dissolved in 100 mL of dioxane and treated withiso-butyl alcohol (6.26 mL, 0.0686 mol), EDC (8.72 g, 0.0457) andcatalytic DMAP (100 mg) at 0° C. After stirring for 17 hours, theorganics were evaporated at reduced pressure, the residue diluted withEtOAc washed with NaHCO₃, brine and dried over Na₂SO₄. Evaporationyields 8.42 g (71%) of an oil. C₁₃H₂₅NO₄ requires: C=60.21, H=9.72, andN=5.40. Anal found: C=59.91, H=9.89, and N=5.67.

[3260] The above N-BOC amino acid ester (8.00 g, 0.032 mol) wasdeprotected as above giving 3.12 g (61%) of the free base as a colorlessoil which solidifies upon standing.

[3261] 2. L-N-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was dissolved in100 mL of CH₂Cl₂, iso-butyl alcohol (21.9 mL, 0.238 mol) and treatedwith DMAP (100 mg) and EDC (10.0 g, 0.52 mol) at 0° C. The mixture wasstirred for 17 hours, diluted with H₂O, washed with 1.0 N HCl, NaHCO₃,then brine and the organics were dried over Na₂SO₄. Filtration andevaporation yields 11.8 g (quantitative) of L-N-BOC alanine iso-butylester which is contaminated with a small amount of solvent. A sample wasvacuum dried for analytical analysis. C₁₂H₂₃NO₄ requires: C=58.79,H=9.38, and N=5.71. Anal found: C=58.73, H=9.55, and N=5.96.

[3262] The above N-BOC amino acid ester (11.8 g, 0.0481 mol) wasdeprotected as above. The free base was converted to the correspondingHCl salt using saturated HCl (g)/EtOAc to give L-N-alanine iso-butylester hydrochloride. Obtained 4.2 g (48%) of a colorless solid.C₇H₁₅NO₂. HCl requires: C=46.28, H=8.88, and N=7.71. Anal found:C=46.01, H =8.85, and N=7.68.

General Procedure BK Methyl ester formation from amino acids

[3263] The amino acid (amino acid or amino acid hydrochloride) issuspended in methanol and chilled to 0° C. HCl gas is bubbled throughthis solution for 5 minutes. The reaction is allowed to warm to roomtemperature then stirred for 4 hours. The solvents are then removed atreduced pressure to afford the desired amino acid methyl esterhydrochloride. This product is usually used without furtherpurification.

Example BA Synthesis of free and polymer bound PEPCN-ethyl-N′-3-(1-pyrrolidinyl)propylurea

[3264] To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250 mLchloroform was added 50 g (0.39 mol) 3-(1-pyrrolidinyl)propylaminedropwise with cooling. Once the addition was complete, the cooling bathwas removed and the reaction mixture stirred at room temperature for 4hours. The reaction mixture was then concentrated under reduced pressureto give 74.5 g (96.4%) of the desired urea as a clear oil.

[3265] 1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)

[3266] To a solution of 31.0 g (0.156 mol)N-ethyl-N′-3-(1-pyrrolidinyl)propylurea in 500 mL dichloromethane wasadded 62.6 g (0.62 mol) triethylamine and the solution was cooled to 0°C. To this solution were then added 59.17 g (0.31 mol) 4-toluenesulfonylchloride in 400 mL dichloromethane dropwise at such a rate as tomaintain the reaction at 0-5° C. After the addition was complete, thereaction mixture was warmed to room temperature and then heated toreflux for 4 hours. After cooling to room temperature, the reactionmixture was washed with saturated aqueous potassium carbonate (3×150mL). The aqueous phases were combined and extracted withdichloromethane. All organic phases were combined and concentrated underreduced pressure. The resultant orange slurry was suspended in 250 mLdiethyl ether and the solution decanted off from the solid. Theslurry/decantation process was repeated 3 more times. The ethersolutions were combined and concentrated under reduced pressure to give18.9 g (67%) of the desired product as a crude orange oil. A portion ofthe oil was distilled under vacuum to give a colorless oil distilling at78-82° C. (0.4 mm Hg).

[3267] Preparation of a polymer supported form of1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)

[3268] A suspension of 8.75 g (48.3 mmol)1-(3-(1-pyrrolidin-yl)propyl)-3-ethylcarbodiimide and 24.17 g (24.17mmol) Merrifield's resin (2% cross-linked, 200-400 mesh,chloromethylated styrene/divinylbenzene copolymer, 1 meq. Cl/g) indimethylformamide was heated at 100° C. for 2 days. The reaction wascooled and filtered and the resulting resin washed sequentially with 1LDMF, 1L THF and 1L diethyl ether. The remaining resin was then driedunder vacuum for 18 hours.

Example BB Preparation of alanine iso-butyl ester hydrochloride

[3269] A mixture of 35.64 g (0.4 mol) of (D,L)-alanine (Aldrich) (orL-alanine (Aldrich)); 44 mL (0.6 mol) of thionyl chloride (Aldrich) and200 mL of isobutanol was refluxed for 1.5 hours and the volatiles wereremoved completely on a rotavapor of 90° C. under reduced pressure togive (D,L)-alanine iso-butyl ester hydrochloride (or L-alanine iso-butylester hydrochloride), which was pure enough to be used for furthertransformations.

Example BC Preparation of 3,5-dichlorophenylacetic acid

[3270] To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in75 mL of dichloromethane at 0° C. was added 1.8 mL of methanesulfonylchloride followed by 3.5 mL of triethylamine added dropwise.After 2 hours the solution was diluted to 150 mL with dichloromethane,washed with 3N HCl, saturated aqueous NaHCO₃ dried with Na₂SO₄ and thesolvents removed to yield the desired 3,5-dichlorobenzylmethanesulfonate as a yellow oil that was used without purification.

[3271] The crude sulfonate was dissolved in 50 mL of DMF at 0° C. andthen 3 g of KCN was added. After 2 hours an additional 50 mL of DMF wasadded and the solution was stirred for 16 hours. The red solution wasdiluted with 1 L of H₂O and acidified to pH 3 with 3N HCl. The aqueoussolution was extracted with dichloromethane. The combined organics werewashed with 3N HCl, dried with Na₂SO₄ and the solvents removed atreduced pressure to yield crude 3,5-dichlorophenylacetonitrile which wasused without purification.

[3272] The nitrile was added to a mixture of 40 mL of concentratedsulfuric acid and 50 mL H₂O and heated to reflux for 48 hours, cooled toroom temperature and stirred for 48 hours. The reaction was diluted into1 L of crushed ice, warmed to room temperature and extracted with 2×200mL of dichloromethane and 2×200 mL of ethylacetate. Both sets oforganics were combined and washed with saturated aqueous NaHCO₃. TheNaHCO₃ fractions were combined and acidified to pH 1 with 3N HCl. Thewhite solid was too fine to filter and was extracted out with 2×200 mLof dichloromethane. The combined organics were dried with Na₂SO₄ and thesolvents removed at reduced pressure to yield crude3,5-dichlorophenylacetic acid as a white solid. The solid was slurriedwith hexane and filtered to get 1.75g of white solid.

[3273] NMR (CDCl₃): (in ppm) 3.61 (s, 2H), 7.19 (s,1H), 7.30 (s, 1H)

Example BD Synthesis of N-(3-chlorophenylacetyl)alanine

[3274] The title compound was prepared using L-alanine (Nova Biochem)and 3-chlorophenyl acetic acid (Aldrich) by following General ProceduresBF or BG, followed by hydrolysis using General Procedure BD.

Example B1 Synthesis of N-(phenylacetyl)-D,L-alanine iso-butyl ester

[3275] Following General Procedure BA above and using phenylacetylchloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (fromExample BB above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[3276] NMR data was as follows:

[3277]¹H-nmr (CDCl₃): δ=7.23-7.36 (m, 5H), 6.18 (d, 1H), 4.58 (t, J=7.3Hz, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.90 (m, 1H), 1.34 (d, J=7.2 Hz,3H), 0.89 (d, J=6.8 Hz, 6H).

[3278]¹³C-nmr (CDCl₃): δ=172.7, 170.3, 134.5, 129.2, 128.8, 127.2, 71.3,48.1, 43.4, 27.5, 18.8, 18.3.

[3279] C₁₅H₂₁NO₃ (MW=263.34; Mass Spectroscopy (MH⁺=264))

Example B2 Synthesis of N-(3-phenylpropionyl)-D,L-alanine iso-butylester

[3280] Following General Procedure BA above and using 3-phenylpropionylchloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (fromExample BB above), the title compound was prepared as a solid having amelting point of from 51°-54° C. The reaction was monitored by tlc onsilica gel and purification was by extraction with Et₂O followed bywashes with aqueous K₂CO₃ and aqueous HCl.

[3281] NMR data was as follows:

[3282]¹H-nmr (CDCl₃): δ=7.25 (m, 2H), 7.19 (m, 3H), 6.28 (d, J=7.2 Hz,1H), H), 4.58 (quint., J=7.2 Hz, 1H), 3.89 (m, 2H), 2.95 (t, J=7.7 Hz,2H), 2.50 (m, 2H), 1.92 (m, 1H), 1.33 (d, J=7.1 Hz, 3H), 0.91 (d, J=6.7Hz, 6H).

[3283]¹³C-nmr (CDCl₃): δ=173.0, 171.5, 140.6, 128.3, 128.1, 126.0, 71.2,47.8, 37.9, 31.4, 27.5, 18.79, 18.77, 18.3.

[3284] C₁₆H₂₃NO₃ (MW=277.37, Mass Spectroscopy (MH⁺278))

Example B3 Synthesis of N-(3-methylpentanoyl)-L-alanine iso-butyl ester

[3285] Following General Procedure BB and using 3-methylpentanoic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BBabove), the title compound was prepared as an oil. The reaction wasmonitored by tlc on silica gel and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[3286] NMR data was as follows:

[3287]¹H-nmr (CDCl₃): δ=6.08 (d, J=5.9 Hz, 1H), 4.62 (quint., J=7.3 Hz,1H), 3.92 (m, 2H), 2.22 (m, 1H), 1.84-2.00 (m, 3H), 1.40 (d, J=7.2 Hz,3H), 1.35 (m, 1H), 1.20 (m, 1H), 0.85-0.96 (m, 12H).

[3288]¹³C-nmr (CDCl₃): δ=173.3, 172.1, 71.4, 47.9, 43.9, 32.3, 29.38,29.35, 27.6, 19.10, 19.06, 18.93, 18.91, 18.72, 18.67, 11.3.

[3289] C₁₃H₂₅NO₃ (MW=243.35, Mass Spectroscopy (MH⁺244))

Example B4 Synthesis of N-[(4-chlorophenyl)acetyl]-L-alanine iso-butylester

[3290] Following General Procedure BB and using 4-chlorophenylaceticacid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from ExampleBB above), the title compound was prepared as a solid having a meltingpoint of 111°-113° C. The reaction was monitored by tlc on silica geland purification was by extraction with Et₂O followed by washes withaqueous K₂CO₃ and aqueous HCl.

[3291] NMR data was as follows:

[3292]¹H-nmr (CDCl₃): δ=7.30 (d, J=8.2 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H),6.18 (d, J=5.5 Hz, 1H), 4.57 (quint., J=7.2 Hz, 1H), 3.88 (m, 2H), 3.53(s, 2H), 1.91 (m, 1H), 1.36 (d, J=7.1 Hz, 3H), 0.90 (d, J=6.8 Hz, 6H).

[3293]¹³C-nmr (CDCl₃): δ=172.8, 169.8, 133.1, 133.0, 130.6, 128.9, 71.4,48.2, 42.6. 27.6, 18.85, 18.82, 18.4.

[3294] C₁₅H₂₀NO₃Cl (MW=297.78, Mass Spectroscopy (MH⁺298))

Example B5 Synthesis of N-[(3,4-dichlorophenyl)acetyl]-L-alanineiso-butyl ester

[3295] Following General Procedure BB and using 3,4-dichlorophenylaceticacid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from ExampleBB above), the title compound was prepared as a solid having a meltingpoint of 81°-83° C. The reaction was monitored by tlc on silica gel andpurification was by extraction with Et₂O followed by washes with aqueousK₂CO₃ and aqueous HCl.

[3296] NMR data was as follows:

[3297]¹H-nmr (CDCl₃): δ=0.90 (d, J=6.8 Hz, 6H), 1.38 (d, J=7.1 Hz, 3H),1.91 (m, 1H), 3.50 (s, 2H), 3.90 (m, 2H), 4.57 (quint., J=7.1 Hz, 1H),6.31 (d, J=4.9 Hz, 1H),7.12 (m, 1H), 7.38 (m, 2H).

[3298]¹³C-nmr (CDCl₃): δ=18.4, 18.8, 18.9, 27.6, 42.2, 48.3, 71.5,128.6, 130.6, 131.2, 131.3, 132.6, 134.7, 169.2, 172.8.

[3299] C₁₅H₁₉NO₃Cl₂ (MW=332.23, Mass Spectroscopy (MH⁺332))

Example B6 Synthesis of N-[(4-methylphenyl)acetyl]-D,L-alanine iso-butylester

[3300] Following General Procedure BB and using 4-methylphenylaceticacid (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (fromExample BB above), the title compound was prepared as a solid having amelting point of 102°-104° C. The reaction was monitored by tlc onsilica gel (Rf=0.6 in 33% ethyl acetate/hexanes) and purification was byextraction with Et₂O followed by washes with aqueous K₂CO₃ and aqueousHCl.

[3301] NMR data was as follows:

[3302]¹H-nmr (CDCl₃): δ=0.90 (d, J=6.7 Hz, 6H), 1.35 (d, J=7.2 Hz, 3H),1.91 (m, 1H), 2.34 (s, 3H), 3.55 (s, 2H), 3.88 (m, 2H), 4.58 (m, 1H),6.05 (bd, 1H), 7.16 (s, 4H).

[3303]¹³C-nmr (CDCl₃): δ=18.5, 18.85, 18.87, 21.0, 27.6, 43.1, 48.1,71.3, 129.2, 129.6, 131.3, 136.9, 170.6, 172.8.

[3304] C₁₆H₂₃NO₃ (MW=277.37, Mass Spectroscopy (MH⁺278))

Example B7 Synthesis of N-[(3-pyridyl)acetyl]-D,L-alanine iso-butylester

[3305] Following General Procedure BF and using 3-pyridylacetic acidhydrochloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride(from Example BB above), the title compound was prepared as a solidhaving a melting point of 62°-64° C. The reaction was monitored by tlcon silica gel (Rf=0.48 10% methanol/dichloromethane) and purificationwas by silica gel chromatography.

[3306] NMR data was as follows:

[3307]¹H-nmr (CDCl₃): δ=8.40 (d, J=2.8, 2H); 7.6 (m, 1H): 7.16 (m, 2H);4.5 (quint., J=7.2, 7.2, 1H); 3.8 (m, 2H); 3.48 (s, 2H); 1.8 (m, 1H);1.30 (d, J=7.2, 3H); 0.81 (d, J=6.7, 6H).

[3308]¹³C-nmr (CDCl₃): δ=173.4, 170.1, 150.6, 148.8, 137.4, 131.4,124.1, 71.9, 48.9, 40.6, 28.1, 19.5, 19.4, 18.6.

[3309] C₁₄H₂₀N₂O₃ (MW=264, Mass Spectroscopy (MH⁺265)) Example B8

Synthesis of N-[(1-naphthyl)acetyl]-L-alanine iso-butyl ester

[3310] Following General Procedure BB and using 1-naphthylacetic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BBabove), the title compound was prepared as a solid having a meltingpoint of 69°-73° C. The reaction was monitored by tlc on silica gel andpurification was by extraction with Et₂O followed by washes with aqueousK₂CO and aqueous HCl.

[3311] NMR data was as follows:

[3312]¹H-nmr (CDCl₃): δ=0.83 (m, 6H), 1.25 (d, J=7.1 Hz, 3H), 1.81 (m,1H), 3.79 (m, 2H), 4.04 (2s, 2H), 4.57 (quint., J=7.3 Hz, 1H), 5.99 (d,J=7.1 Hz 1H), 7.44 (m, 2H), 7.53 (m, 2H), 7.85 (m, 2H), 7.98 (m, 1H).

[3313]¹³C-nmr (CDCl₃): δ=18.2, 18.81, 18.83, 27.5, 41.5, 48.2, 71.3,123.7, 125.6, 126.1, 126.6, 128.2, 128.5, 128.7, 130.7, 132.0, 133.9,170.3, 172.5.

[3314] C₁₉H₂₃NO₃ (MW=313.40, Mass Spectroscopy (MH⁺314))

Example B9 Synthesis of N-[(2-naphthyl)acetyl]-L-alanine iso-butyl ester

[3315] Following General Procedure BB and using 2-naphthylacetic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BBabove), the title compound was prepared as a solid having a meltingpoint of 128°-129° C. The reaction was monitored by tlc on silica geland purification was by extraction with Et₂O followed by washes withaqueous K₂CO₃ and aqueous HCl.

[3316] NMR data was as follows:

[3317]¹H-nmr (CDCl₃): δ=0.86 (m, 6H), 1.35 (d, J=7.1 Hz, 3H), 1.78 (m,1H), 3.76 (s, 2H), 3.87 (m, 2H), 4.62 (quint., J=7.2 Hz, 1H), 6.13 (d,J=7.1 Hz, 1H), 7.41 (m, 1H), 7.48 (m, 2H), 7.74 (s, 1H), 7.83 (m, 3H).

[3318]¹³C-nmr (CDCl₃): δ=18.4, 18.82, 18.85, 27.6, 43.7, 48.2, 71.4,125.9, 126.3, 127.2, 127.6, 127.7, 128.2, 128.7, 132.0, 132.5, 133.5,170.3, 172.8.

[3319] C₁₉H₂₃NO₃ (MW=313.40, Mass Spectroscopy (MH⁺314)).

Example B10 Synthesis of N-(4-phenylbutanoyl)-L-alanine iso-butyl ester

[3320] Following General Procedure BB and using 4-phenylbutanoic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BBabove), the title compound was prepared as an oil. The reaction wasmonitored by tlc on silica gel and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[3321] NMR data was as follows:

[3322]¹H-nmr (CDCl₃): δ=0.92 (d, J=6.7 Hz, 6H), 1.38 (d, J=7.1 Hz, 3H),1.96 (m, 3H), 2.21 (t, J=7.1 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 3.90 (m,2H), 4.59 (quint., J=7.2 Hz, 1H), 6.31 (d, 1H), 7.16 (m, 3H), 7.24 (m,2H).

[3323]¹³C-nmr (CDCl₃): δ=18.3, 18.75, 18.78, 26.8, 27.5, 34.9, 35.3,47.8, 71.2, 125.7, 128.2, 128.3, 141.3, 172.1, 173.0.

[3324] C₁₇H₂₅NO₃ (MW=291.39, Mass Spectroscopy (MH⁺292)).

Example B11 Synthesis of N-(5-phenylpentanoyl)-L-alanine iso-butyl ester

[3325] Following General Procedure BB and using 5-phenylpentanoic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BBabove), the title compound was prepared as an oil. The reaction wasmonitored by tlc on silica gel and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[3326] NMR data was as follows:

[3327]¹H-nmr (CDCl₃): δ=7.23 (m, 2H), 7.17 (m, 3H), 6.30 (d, 1H), 4.59(quint., J=7.3 Hz, 1H), 3.91 (m, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.22 (t,J=7.2 Hz, 2H), 1.93 (m, 1H), 1.66 (m, 4H), 1.38 (d, J=7.2 Hz, 3H), 0.92(d, J=6.7 Hz 6H).

[3328]¹³C-nmr (CDCl₃): 8 173.1, 172.3, 142.0, 128.2, 128.1, 125.6, 71.2,47.8, 36.1, 35.5, 30.8, 27.5, 25.0, 18.80, 18.77, 18.4.

[3329] C₁₈H₂₇NO₃ (MW=305.39, Mass Spectroscopy (MH⁺306)).

Example B12 Synthesis of N-[(4-pyridyl)acetyl]-D,L-alanine iso-butylester

[3330] Following General Procedure BF and using 4-pyridylacetic acidhydrochloride (Aldrich) and (D,L)-alanine iso-butyl ester hydrochloride(from Example BB above), the title compound was prepared as a solidhaving a melting point of 64°-66° C. The reaction was monitored by tlcon silica gel (Rf=0.43 10% methanol/dichloromethane) and purificationwas by silica gel chromatography.

[3331] NMR data was as follows:

[3332]¹H-nmr (CDCl₃): δ=8.51 (dd, J=1.6, 2.8, 1.6, 2H); 7.23 (dd, J=4.3,1.6, 4.4, 2H); 6.71 (d, J=6.8, 1H); 4.56 (quint., J=7.3, 7.2, 1H); 3.88(m, 2H); 3.53 (s, 2H); 1.89 (m, 1H); 1.36 (d, J=7.2, 3H); 0.88 (d,J=6.7, 6H).

[3333]¹³C-nmr (CDCl₃): δ=173.5, 169.3, 150.5, 144.4, 125.1, 72.1, 48.9,43.0, 28.2, 19.5, 19.5, 18.9.

[3334] C₁₄H₂₀N₂O₃ (MW=264, Mass Spectroscopy (MH⁺265))

Example B13 Synthesis of N-(phenylacetyl)-L-alanine iso-butyl ester

[3335] Following General Procedure BB and using phenylacetyl chloride(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BBabove), the title compound was prepared as a solid having a meltingpoint of 45°-47° C. The reaction was monitored by tlc on silica gel andpurification was by extraction with Et₂O followed by washes with aqueousK₂CO₃ and aqueous HCl.

[3336] NMR data was as follows:

[3337]¹H-nmr (CDCl₃): δ=7.24-7.39 (m, 5H), 6.14 (d, 1H), 4.58 (t, J=7.3Hz, 1H), 3.88 (m, 2H), 3.58 (s, 2H), 1.90 (m, 1H), 1.35 (d, J=7.2 Hz,3H), 0.89 (d, J=6.7 Hz, 6H).

[3338]¹³C-nmr (CDCl₃): δ=172.8, 170.4, 134.5, 129.3, 128.9, 127.2, 71.3,48.1, 43.5, 27.5, 18.9, 18.8, 18.4.

[3339] C₁₅H₂₁NO₃ (MW=263.34, Mass Spectroscopy (MH⁺264)).

Example B14 Synthesis of 2-[(3,4-dichlorophenyl)acetamido]butyric acidiso-butyl ester

[3340] Following General Procedure BI above and using3,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above) the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3341] NMR data was as follows:

[3342]¹H-nmr (CDCl₃): δ=7.36 (m, 3H), 6.03 (bd, 1H), 4.54 (m, 1H), 3.87(m, 2H), 3.49 (s, 2H), 1.93 (m, 2H), 1.72 (m, 1H), 0.88 (d, 6H), 0.80(t, 3H).

Example B15 Synthesis of 2-1(3-methoxyphenyl)acetamido]butyric acidiso-butyl ester

[3343] Following General Procedure BI above and using3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3344] NMR data was as follows:

[3345]¹H-nmr (CDCl₃): δ=6.75 (m, 4H), 5.93 (bd, 1H), 4.51 (m, 1H), 3.83(m, 2H), 3.75 (s, 2H), 3.52 (s, 2H), 1.82 (m, 2H), 1.60 (m, 1H), 0.84(d, 6H), 0.74 (t, 3H).

[3346] C₁₇H₂₅NO₄ (MW=307.39, Mass Spectroscopy (MH⁺309)).

Example B16 Synthesis of 2-[(4-nitrophenyl)acetamido]butyric acidiso-butyl ester

[3347] Following General Procedure BI above and using4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3348] NMR data was as follows:

[3349]¹H-nmr (CDCl₃): δ=8.16 (d, 2H), 7.44 (d, 2H), 6.04 (bd, 1H), 4.55(m, 1H), 3.86 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.67 (m, 1H), 0.85(d, 6H), 0.85 (t 3H).

[3350] C₁₆H₂₂N₂O₅ (MW=322.36, Mass Spectroscopy (MH⁺323)).

Example B17 Synthesis of 2-[(3,4-methylenedioxyphenyl)acetamido]butyricacid iso-butyl ester

[3351] Following General Procedure BI above and using3,4-(methylenedioxy)-phenyl acetic acid (Aldrich) and iso-butyl2-aminobutyrate (prepared following General Procedure BJ above), thetitle compound was prepared. The reaction was monitored by tlc on silicagel and purification was by filtration as described in the generalprocedure.

[3352] NMR data was as follows:

[3353]¹H-nmr (CDCl₃): δ=6.72 (m, 3H), 5.92 (bd, 1H), 4.54 (m, 1H), 3.86(m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.66 (m, 1H), 0.89 (d, 6H), 0.79(t, 3H).

Example B18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butylester

[3354] Following General Procedure BI above and using 3-thiopheneaceticacid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following GeneralProcedure BJ above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by filtration asdescribed in the general procedure.

[3355] NMR data was as follows:

[3356]¹H-nmr (CDCl₃): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05(bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91(d, 6H), 0.86 (t, 3H).

Example B19 Synthesis of 2-[(4-chlorophenyl)acetamido]butyric acidiso-butyl ester

[3357] Following General Procedure BI above and using4-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3358] NMR data was as follows:

[3359]¹H-nmr (CDCl₃): δ=7.22 (m, 2H), 7.11 (m, 2H), 5.80 (m, 1H), 4.44(m, 1H), 3.78 (m, 2H), 3.43 (s, 2H), 1.77 (m, 2H), 1.56 (m, 1H), 0.83(d, 6H) 0.71 (t, 3H).

Example B20 Synthesis of 2-[(3-nitrophenyl)acetamido]butyric acidiso-butyl ester

[3360] Following General Procedure BI above and using3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3361] NMR data was as follows:

[3362]¹H-nmr (CDCl₃): δ=8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46(m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98(d, 6H) 0.71 (t, 3H).

Example B21 Synthesis of 2-[(2-hydroxyphenyl)acetamido]butyric acidiso-butyl ester

[3363] Following General Procedure BI above and using2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3364] NMR data was as follows:

[3365]¹H-nmr (CDCl₃): δ=7.14 (m, 1H), 7.01 (m, 1H), 6.93 (m, 1H), 6.79(m, 1H), 6.46 (m, 1H), 4.51 (m, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 2.01(m, 2H), 1.75 (m, 1H), 0.89 (d, 6H), 0.85 (t, 3H).

Example B22 Synthesis of 2-[(2-naphthyl)acetamido]butyric acid iso-butylester

[3366] Following General Procedure BI above and using 2-naphthylaceticacid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following GeneralProcedure BJ above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by filtration asdescribed in the general procedure.

[3367] NMR data was as follows:

[3368]¹H-nmr (CDCl₃): δ=7.83 (m, 7H), 5.95 (m, 1H), 4.58 (m, 1H), 3.84(m, 2H), 3.75 (s, 2H), 1.89 (m, 2H), 1.63 (m, 1H), 0.91 (d, 6H), 0.81(t, 3H).

[3369] C₂₀H₂₅NO₃ (MW=327.42, Mass Spectroscopy (MH⁺328)).

Example B23 Synthesis of 2-[(2,4-dichlorophenyl)acetamido]butyric acidiso-butyl ester

[3370] Following General Procedure BI above and using2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3371] NMR data was as follows:

[3372]¹H-nmr (CDCl₃): δ=7.49 (m, 1H), 7.22 (m, 2H) 5.98 (m, 1H), 4.52(m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, 1H) 0.87 (d,6H), 0.80 (t, 3H).

Example B24 Synthesis of 2-[(4-bromophenyl)acetamido]butyric acidiso-butyl ester

[3373] Following General Procedure BI above and using4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3374] NMR data was as follows:

[3375]¹H-nmr (CDCl₃): δ=7.43 (d, 2H), 7.19 (d, 2H) 5.85 (m, 1H), 4.51(m, 1H), 3.81 (m, 2H), 3.47 (s, 2H), 1.84 (m, 2H), 1.61 (m, 1H) 0.84 (d,6H), 0.76 (t, 3H).

[3376] C₁₆H₂₂NO₃Br (MW=356.26, Mass Spectroscopy (MH⁺358)).

Example B25 Synthesis of 2-[(3-chlorophenyl)acetamido])butyric acidiso-butyl ester

[3377] Following General Procedure BI above and using3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3378] NMR data was as follows:

[3379]¹H-nmr (CDCl₃): δ=7.25 (m, 3H), 7.12 (m, 1H) 5.80 (m, 1H), 4.52(m, 1H), 3.86 (m, 2H), 3.50 (s, 2H), 1.87 (m, 2H), 1.67 (m, 1H) 0.88 (d,6H), 0.77 (t, 3H).

[3380] C₁₆H₂₂NO₃Cl (MW=311.81 Mass Spectroscopy (MH⁺313)).

Example B26 Synthesis of 2-[(3-fluorophenyl)acetamido]butyric acidiso-butyl ester

[3381] Following General Procedure BI above and using3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3382] NMR data was as follows:

[3383]¹H-nmr (CDCl₃): δ=7.31 (m, 1H), 7.01 (m, 3H) 5.95 (m, 1H), 4.54(m, 1H), 3.84 (m, 2H), 3.54 (s, 2H), 1.88 (m, 2H), 1.65 (m, 1H) 0.87 (d,6H), 0.81 (t, 3H).

[3384] C₁₆H₂₂NO₃F (MW=295.35 Mass Spectroscopy (MH⁺296)).

Example B27 Synthesis of 2-[(benzothiazol-4-yl)acetamido]butyric acidiso-butyl ester

[3385] Following General Procedure BI above and using4-benzothiazol-4-yl acetic acid (Chemservice) and iso-butyl2-aminobutyrate (prepared following General Procedure BJ above), thetitle compound was prepared. The reaction was monitored by tlc on silicagel and purification was by filtration as described in the generalprocedure.

[3386] NMR data was as follows:

[3387]¹H-nmr (CDCl₃): δ=7.82 (m, 1H), 7.51-7.21 (m, 4H) 5.84 (m, 1H),4.51 (m, 1H), 3.90 (s, 2H), 3.79 (m, 2H), 1.78 (m, 2H), 1.58 (m, 1H)0.80 (d, 6H), 0.66 (t, 3H).

Example B28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acidiso-butyl ester

[3388] Following General Procedure BI above and using2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3389] NMR data was as follows:

[3390]¹H-nmr (CDCl₃): δ=7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85(m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H) 0.87 (d,6H), 0.77 (t, 3H).

[3391] C₁₇H₂₅NO₃ (MW=291.39 Mass Spectroscopy (M+291)).

Example B29 Synthesis of 2-[(2-fluorophenyl)acetamido]butyric acidiso-butyl ester

[3392] Following General Procedure BI above and using2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3393] NMR data was as follows:

[3394]¹H-nmr (CDCl₃): δ=7.28 (m, 1H), 7.09 (m, 3H) 6.03 (m, 1H), 4.54(m, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.89 (m, 2H), 1.64 (m, 1H) 0.88 (d,6H), 0.80 (t, 3H).

Example B30 Synthesis of 2-[(4-fluorophenyl)acetamido]butyric acidiso-butyl ester

[3395] Following General Procedure BI above and using4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3396] NMR data was as follows:

[3397]¹H-nmr (CDCl₃): δ=7.20 (m, 2H), 6.97 (m, 2H) 5.87 (m, 1H), 4.492(m, 1H), 3.83 (m, 2H), 3.48 (s, 2H), 1.86 (m, 2H), 1.60 (m, 1H) 0.87 (d,6H), 0.78 (t, 3H).

[3398] C₁₆H₂₂NO₃F (MW=295.35 Mass Spectroscopy (MH⁺296)).

Example B31 Synthesis of 2-[(3-bromophenyl)acetamido]butyric acidiso-butyl ester

[3399] Following General Procedure BI above and using3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3400] NMR data was as follows:

[3401]¹H-nmr (CDCl₃): δ=7.45 (m, 2H), 7.23 (m, 2H) 5.95 (m, 1H), 4.55(m, 1H) 3.84 (m, 2H) 3.55 (s, 2H), 1.89 (m, 2H), 1.68 (m, 1H) 0.91 (d,6H), 0.81 (t, 3H).

[3402] C₁₆H₂₂NO₃Br (MW=356.26 Mass Spectroscopy (M⁺357)).

Example B32 Synthesis of 2-[(3-trifluoromethylphenyl)acetamido]butyricacid iso-butyl ester

[3403] Following General Procedure BI above and using3-trifluoromethyl-phenylacetic acid (Aldrich) and iso-butyl2-aminobutyrate (prepared following General Procedure BJ above), thetitle compound was prepared. The reaction was monitored by tlc on silicagel and purification was by filtration as described in the generalprocedure.

[3404] NMR data was as follows:

[3405]¹H-nmr (CDCl₃): δ=7.52 (m, 1H), 7.47 (m, 2H) 6.01 (m, 1H), 4.56(m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, 1H) 0.87 (d,6H), 0.80 (t, 3H).

[3406] C₁₇H₂₂NO₃F₃ (MW=345.36 Mass Spectroscopy (MH⁺345)).

Example B33 Synthesis of 2-[(2-thienyl)acetamido]butyric acid iso-butylester

[3407] Following General Procedure BI above and using 2-thiopheneaceticacid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following GeneralProcedure BJ above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by filtration asdescribed in the general procedure.

[3408] NMR data was as follows:

[3409]¹H-nmr (CDCl₃): δ=6.89 (m, 3H), 6.07 (bd, 1H), 4.50 (m, 1H), 3.82(m, 2H), 3.71 (s, 2H), 1.85 (m, 2H), 1.62 (m, 1H), 0.81 (d, 6H), 0.75(t, 3H).

[3410] C₁₄H₂₁NO₃S (MW=283.39, Mass Spectroscopy (MH⁺284)).

Example B34 Synthesis of 2-(phenylacetamido)butyric acid iso-butyl ester

[3411] Following General Procedure BH above and using phenylacetic acid(Aldrich) and iso-butyl 2-aminobutyrate (prepared following GeneralProcedure BJ above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by chromatography onsilica gel using 9:1 toluene:EtOAc as the eluant.

[3412] NMR data was as follows:

[3413]¹H-nmr (CDCl₃): δ=7.17-7.28 (m, 5H), 6.23 (bd, 1H), 4.51 (m, 1H),3.86 (m, 2H), 3.54 (s, 2H), 1.87 (m, 2H), 1.62 (m, 1H), 0.87 (d, 6H),0.78 (t, 3H).

[3414] C₁₆H₂₃NO₃ (MW=277.36, Mass Spectroscopy (MH⁺277)).

Example B35 Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester

[3415] Step A. Preparation of N-(phenylacetyl) valine

[3416] To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in50 mL (100 mmol) of 2N NaOH cooled to 0° C. was added dropwise 5.3 mL(40 mmol) of phenylacetyl chloride (Aldrich). A colorless oilprecipitated. The reaction mixture was allowed to warm to roomtemperature and stirred for 18 hours, washed with 50 mL diethyl ether,acidified to pH 2-3 with aqueous HCl. The white precipitate formed wasfiltered off, washed thoroughly with water, followed by diethyl ether togive 7.1 g (30 mmol, 69% yield) of the title compound.

[3417] NMR data was as follows:

[3418]¹H-nmr (DMSO-d₆): δ=12.63 (s, 1H), 8.25 (d, J=8.6Hz, 1H), 7.27 (m,5H), 4.15 (m, 1H), 3.56 (d, J=13.8Hz, 1H), 3.47 (d, J=13.8Hz, 1H), 2.05(m, 1H), 0.87 (d, J=6.8,Hz, 3H), 0.84 (d, J=6.8Hz, 3)

[3419]¹³C-nmr (DMSO-d₆): δ=173.2, 170.4, 136.6, 129.0, 128.2, 126.3,57.1, 41.9, 30.0, 19.2, 18.0

[3420] C₁₃H₁₇NO₃ (MW=235.29; Mass Spectroscopy (MH⁺=236))

[3421] Step B. Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester

[3422] Following General Procedure BC and using the N-(phenylacetyl)valine prepared in Step A above and 2-methylbutan-1-ol (Aldrich), thetitle compound was prepared as a diastereomeric mixture. The reactionwas monitored by tlc on silica gel and purification was by filtration asdescribed in the general procedure.

[3423] NMR data was as follows:

[3424]¹H-nmr (CDCl₃): δ=7.25-7.40 (m, 5H), 5.95 (d, 1H), 4.56 (m, 1H),3.84-4.00 (m, 2H), 3.61 (s, 2H), 2.10 (m, 1H), 1.68 (m, 1H), 1.38 (m,1H), 1.15 (m 1H), 0.82-0.94 (m, 9H), 0.76 (d, 3H).

[3425]¹³C-nmr (CDCl₃): δ=171.84, 171.81, 170.7, 134.6, 129.31, 129.27,128.9, 127.3, 69.8, 57.0, 43.7, 33.9, 31.3,25.9, 25.8, 18.9, 17.4,16.34, 16.27, 11.12, 11.07.

[3426] C₁₈H₂₇NO₃ (MW=305.42, Mass Spectroscopy (MH 306)).

Example B36 Synthesis of N-(phenylacetyl)-L-methionine iso-butyl ester

[3427] L-Methionine (0.129 g, 0.869 mmols) (Aldrich) was taken-up indioxane (5.0 mL) and treated with a saturated solution of sodiumbicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114mL, 0.822 mmols). After stirring for 17 hours at room temperature themixture was diluted with ethyl acetate, the layers separated and theaqueous layer acidified to pH 2 with 5N HCl. The crude product wasextracted into ethyl acetate, dried over sodium sulfate, vacuum driedand used without further purification. N-phenylacetyl-L-methionine(0.1285 g, 0.447 mmol) was dissolved in 3.0 mL dioxane and iso-butylalcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), andcatalytic DMAP (0.015 g). After stirring for 17 hours at 23° C., themixture was evaporated at reduced pressure to an oil, the residue wasdiluted in EtOAc and washed with 0.1 N HCl and saturated sodiumbicarbonate. Chromatography on silica gel using 98:2 CHCl₃/MeOH aseluant provided the pure product.

[3428] NMR data was as follows:

[3429]¹H-nmr (CDCl₃): δ=7.4-7.23 (m, 5H), 6.14 (bd, 1H), 4.70 (m, 1H),3.89 (d, 2H), 3.62 (s, 2H), 2.43 (m, 2H), 2.12 (m, 1H), 1.93 (m, 2H),0.94 (d, 6H).

[3430] C₁₇H₂₅NO₃S (MW=323.17, Mass Spectroscopy (M⁻323)

Example B37 Synthesis of N-(phenylacetyl)-L-leucine iso-butyl ester

[3431] L-Leucine (Aldrich) (0.1 14 g, 0.869 mmols) was taken-up indioxane (5.0 mL) and treated with a saturated solution of sodiumbicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114mL, 0.822 mmols). After stirring for 17 hours at room temperature themixture was diluted with ethyl acetate, the layers separated and theaqueous layer acidified to pH 2 with 5N HCl. The crude product wasextracted into ethyl acetate, dried over sodium sulfate, vacuum driedand used without further purification.

[3432] N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in2.0 mL CHCl₃ (EtOH free) and iso-butyl alcohol (0.055 mL) and treatedwith P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for4 days, filtered through a plug of cotton and the filtrate evaporated atreduced pressure to an oil which was sufficiently pure for testing.

[3433] NMR data was as follows:

[3434]¹H-nmr (CDCl₃): δ=7.22 (m, 5H), 5.57 (d, 1H), 4.35 (m, 1H), 3.35(m, 3H), 1.35 (m, 4H), 0.68 (m, 9H).

[3435] C₁₈H₂₇NO₃ (MW=305.40, Mass Spectroscopy (M⁺305)).

Example B38 Synthesis of N-[(3-chlorophenyl)acetyl]alanine3-methylbut-2-enyl ester

[3436] Following General Procedure BC above and usingN-(3-chlorophenylacetyl alanine (from Example BD above) and3-methylbut-2-en-1-ol (Aldrich), the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 30% EtOAc/hexane as the eluant.

[3437] NMR data was as follows:

[3438]¹H-nmr (CDCl₃): δ=7.39-7.16 (m, 4H), 6.06 (bd, 1H), 5.38-5.29 (m,1H), 4.63 (d, J=9Hz, 2H), 3.56 (s, 2H), 1.79 (s, 3H), 1.7 (s, 3H), 1.39(d, J=9 Hz, 3H).

Example B39 Synthesis of N-[(3-chlorophenyl)acetyl]alaninecyclopropylmethyl ester

[3439] Following General Procedure BC above, and usingN-(3-chlorophenylacetyl alanine (from Example BD above) andcyclopropylmethanol (Aldrich), the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[3440] NMR data was as follows:

[3441]¹H-nmr (CDCl₃): δ=7.2-7.1 (m, 4H), 6.09 (bs, 1H), 4.6 (dq, J=9Hz,1H), 3.96 (dd, J=9 Hz, 2H), 3.59 (s, 2H), 1.2 (d, J=9 Hz, 3H), 1.2-1.0(m, 1H), 0.603-0.503 (m, 2H), 0.300-0.203 (m, 2H).

Example B40 Synthesis of N-[(3-chlorophenyl)acetyl]alanine2-thienylmethyl ester

[3442] Following General Procedure BC above, and usingN-(3-chlorophenylacetyl alanine (from Example BD above) and2-thiophenemethanol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[3443] NMR data was as follows:

[3444]¹H-nmr (CDCl₃): δ=7.37-6.97 (m, 7H), 5.97 (q, J=14 Hz, 2H), 4.6(dq, J=9 Hz, 1H), 3.76 (s, 2H), 1.38 (d, J=9 Hz, 3H).

Example B41 Synthesis of N-[(3-chlorophenyl)acetyl]alanine(1-methylcyclopropyl)methyl ester

[3445] Following General Procedure BC above, and usingN-(3-chlorophenylacetyl alanine (from Example BD above) and(1-methylcyclopropyl)methanol (Aldrich) the title compound can beprepared. The reaction was monitored by tlc on silica gel andpurification was by liquid chromatography using 3:7 EtOAc:hexane as theeluant.

[3446] NMR data was as follows:

[3447]¹H-nmr (CDCl₃): δ=8.6 (bd, J=9 Hz, 1H), 3.86 (q, J=14 Hz, 2H), 3.4(s, 2H), 2.29 (q, J=9 Hz, 1H), 1.3 (d, J=9 Hz, 3H), 1.03 (s, 3H),0.5-0.4 (m, 2H), 0.4-0.28 (m, 2H).

Example B42 Synthesis of N-[(3-chlorophenyl)acetyl]alanine3-thienylmethyl ester

[3448] Following General Procedure BC above, and usingN-(3-chlorophenylacetyl alanine (from Example BD above) and3-thiophenemethanol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[3449] NMR data was as follows:

[3450]¹H-nmr (CDCl₃): δ=8.03 (bd, J=9 Hz, 1H), 7.56-7.5 (m, 1H), 7.47(bs, 1H), 7.4-7.17 (m, 4H), 7.06 (d, J=9 Hz, 1H), 5.1 (s, 2H), 4.3 (dq,1H), 1.3 (d, J=9 Hz, 3H).

Example B43 Synthesis of N-[(3-chlorophenyl)acetyl]alanine2-methylcyclopentyl ester

[3451] Following General Procedure BC above, and usingN-(3-chlorophenylacetyl alanine (from Example BD above) and2-methylcyclopentanol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[3452] NMR data was as follows:

[3453]¹H-nmr (CDCl₃): δ=7.39-7.16 (m, 4H), 6.3 (bd, 1H), 4.79-4.7 (m,1H), 4.6-4.25 (m, J=9 Hz, 1H), 3.577 (s, 2H), 2.09-1.8 (m, 2H), 1.74-1.6(m, 2H), 1.39 (dd, J=9 Hz, 3H), 1.2 (dt, J=9 Hz, 1H), 0.979 (dd, J=9 Hz,2H)

[3454] C₁₇H₂₂NO₃Cl (MW=323.82, Mass Spectroscopy (MH⁺323).

Example B44 Synthesis of N-[(3-chlorophenyl)acetyl]alanine2-methylprop-2-enyl ester

[3455] Following General Procedure BC above, and usingN-(3-chlorophenylacetyl alanine (from Example BD above) and2-methylprop-2-en-1-ol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[3456] NMR data was as follows:

[3457]¹H-nmr (CDCl₃): δ=7.39-7.16 (m, 4H), 6.03 (bs, 1H), 4.77 (s, 2H),4.7-4.29 (m, 3H), 2.59 (s, 2H), 1.73 (s, 3H), 1.43 (d, J=9 Hz, 3H)

[3458] C₁₅H₁₈NO₃Cl (MW=295.76, Mass Spectroscopy (MH⁺295)).

Example B45 Synthesis of N-[(3-chlorophenyl)acetyl]alaninecyclohex-2-enyl ester

[3459] Following General Procedure BC above, and usingN-(3-chlorophenylacetyl alanine (from Example BD above) andcyclohex-2-en-1-ol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[3460] NMR data was as follows:

[3461]¹H-nmr (CDCl₃): δ=8.6 (bd, J=9 Hz, 1H), 7.4-7.2 (m, 4H), 6.0-5.8(m, 1H), 5,7-5.5 (m, 1H), 5.1 (bs, 1H), 4.13-4.29 (m, 1H), 3.5 (s, 2H),2.1-1.9 (m, 2H), 1.8-1.69 (m, 1H), 1.69-1.49 (m, 4H), 1.3 (dd, J=9 Hz,3H)

[3462] C₁₇H₂₀NO₃Cl (MW=321.8, Mass Spectroscopy (MH⁺321.2)).

Example B46 Synthesis of N-[(2-phenylbenzoxazol-5-yl)acetyl]alanineiso-butyl ester

[3463] Following General Procedure BI above, and using5-(2-phenylbenzoxazol)-yl-acetic acid (CAS# 62143-69-5) and alanineiso-butyl ester (prepared following General Procedure BJ above), thetitle compound was prepared.

[3464] NMR data was as follows:

[3465]¹H-nmr (CDCl₃): δ=8.24 (m, 3H), 7.68 (m, 1H), 7.51 (m, 5H), 6.04(m, 1H), 4.58 (m, 1H), 3.85 (m, 2H), 3.68 (s, 2H), 1.9 (m, 1H), 1.35 (d,3H), 0.87 (d, 6H).

[3466] C₂₂H₂₄N₂O₄ (MW=380, Mass Spectroscopy (MH⁺381)).

Example B47 Synthesis of N-[(3-methylthiophenyl)acetyl]alanine iso-butylester

[3467] Following General Procedure BI above, and using3-methylthiophenylacetic acid (CAS# 18698-73-2) and alanine iso-butylester (prepared following General Procedure BJ above), the titlecompound was prepared. The reaction was monitored by tlc on silica geland purification was by filtration as described in the generalprocedure.

[3468] NMR data was as follows:

[3469]¹H-nmr (CDCl₃): δ=7.14 (m, 2H), 7.01 (m, 1H), 4.56 (m, 1H), 3.88(m, 2H), 3.54 (s, 2H), 2.46 (s, 3H), 1.89 (m, 1H), 1.35 (d, 3H) 0.85 (d,6H).

[3470] C₁₆H₂₃NO₃S (MW=309, Mass Spectroscopy (MH⁺310)).

Example B48 Synthesis of N-4-[(2-furyl)acetyl]alanine iso-butyl ester

[3471] Following General Procedure BI above, and using 2-furylaceticacid (CAS# 2745-26-8) and alanine iso-butyl ester (prepared followingGeneral Procedure BJ above), the title compound was prepared. Thereaction was monitored by tlc on silica gel and purification was byfiltration as described in the general procedure.

[3472] NMR data was as follows:

[3473]¹H-nmr (CDCl₃): δ=7.36 (m, 1H), 6.34 (m, 1H), 6.21 (m, 1H), 4.56(m, 1H), 3.91 (m, 2H), 3.61 (s, 2H), 1.92 (m, 1H), 1.38 (d, 3H) 0.89 (d,6H).

[3474] C₁₃H₁₉NO₄ (MW=253, Mass Spectroscopy (MH⁺254)).

Example B49 Synthesis of N-[(benzofuran-2-yl)acetyl]alanine iso-butylester

[3475] Following General Procedure BI above, and usingbenzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3476] NMR data was as follows:

[3477]¹H-nmr (CDCl₃): δ=7.51 (m, 1H), 7.44 (m, 1H),7.25 (m, 2H), 6.67(s, 1H), 4:60 (m, 1H), 3.87 (m, 2H), 3.77 (s, 2H), 1.88 (m, 1H), 1.38(d, 3H), 0.87 (d, 6H).

[3478] C₁₇H₂₁NO₄ (MW=303, Mass Spectroscopy (MH⁺304)).

Example B50 Synthesis of N-[(benzothiophen-3-yl)acetyl]alanine iso-butylester

[3479] Following General Procedure BI above, and usingthianaphthen-3-ylacetic acid (Lancaster) and alanine iso-butyl ester(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3480] NMR data was as follows:

[3481]¹H-nmr (CDCl₃): δ=7.89 (m, 1H), 7.76 (m, 1H), 7.38 (m, 3H), 6.07(m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.82 (s, 4H), 1.84 (m, 1H), 1.32(d, 3H) 0.85 (d, 6H).

[3482] C₁₇H₂₁NO₃S (MW=319, Mass Spectroscopy (MH⁺320)).

Example B51 Synthesis of N-[(2-chloro-5-thienyl)acetyl]alanine iso-butylester

[3483] Following General Procedure BI above, and using5-chloro-2-thienyl)acetic acid (CAS# 13669-19-7) and alanine iso-butylester (prepared following General Procedure BJ above), the titlecompound was prepared. The reaction was monitored by tlc on silica geland purification was by filtration as described in the generalprocedure.

[3484] NMR data was as follows:

[3485]¹H-nmr (CDCl₃): δ=6.77 (m, 1H), 6.68 (d, 1H), 6.31 (bm, 1H), 4.59(m, 1H), 3.91 (m, 2H), 3.38 (s, 2H), 1.90 (m, 1H), 1.39 (d, 3H) 0.89 (d,6H).

[3486] C₁₃H₁₈NO₃SCl (MW=303, Mass Spectroscopy (MH⁺303)).

Example B52 Synthesis of N-[(3-methylisoxazol-5-yl)acetyl]alanineiso-butyl ester

[3487] Following General Procedure BI above, and using(3-methyl-isoxazol-5-yl)acetic acid (CAS# 19668-85-0) and alanineiso-butyl ester (prepared following General Procedure BJ above), thetitle compound was prepared. The reaction was monitored by tlc on silicagel and purification was by filtration as described in the generalprocedure.

[3488] NMR data was as follows:

[3489]¹H-nmr (CDCl₃): δ=6.07 (s, 2H), 4.56 (m, 1H), 3.92 (m, 2H), 3.68(s, 2H), 2.29 (s, 3H), 1.94 (m, 1H), 1.89 (d, 3H) 0.91 (d, 6H).

[3490] C₁₃H₂₀N₂O₄ (MW=268, Mass Spectroscopy (MH⁺269)).

Example B53 Synthesis of N-[(2-phenylthiothienyl)acetyl]alanineiso-butyl ester

[3491] Following General Procedure BI above, and using(2-phenyl-thiothienyl)acetic acid and alanine iso-butyl ester (preparedfollowing General Procedure BJ above), the title compound was prepared.The reaction was monitored by tlc on silica gel and purification was byfiltration as described in the general procedure.

[3492] NMR data was as follows:

[3493]¹H-nmr (CDCl₃): δ=7.21-7.11 (m, 6H), 6.92 (d, 1H), 4.56(m, 1H),3.87 (m, 2H), 3.72 (s. 2H), 1.94 (m, 1H), 1.38 (d, 3H) 0.89 (d, 6H).

[3494] C₁₉H₂₃NO₃S₂ (MW=377, Mass Spectroscopy (MH⁺378)).

Example B54 Synthesis of N-[(6-methoxybenzothiophen-2-yl)acetyl]alanineiso-butyl ester

[3495] Following General Procedure BI above, and using(6-methoxythianaphthen-2-yl)acetic acid and alanine iso-butyl ester(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3496] NMR data was as follows:

[3497]¹H-nmr (CDCl,): δ=7.59 (d, 1H), 7.33 (d, 1H), 7.16 (s, 1H), 7.03(dd, 1H), 4:56 (m, 1H), 3.87(s, 3H), 3.84 (m, 2H), 3.76 (s, 2H); 1.85(m, 1H), 1.30 (d, 3H) 0.86 (d, 6H).

[3498] C₁₈H₂₃NO₄S (MW 349, Mass Spectroscopy (MH⁺350)).

Example B55 Synthesis ofN-[(3-phenyl-1,2,4-thiadiazol-5-yl)acetyl]alanine iso-butyl ester

[3499] Following General Procedure BI above, and using(3-phenyl-1,2,4-thiadiazol-5-yl)acetic acid (CAS# 90771-06-5) andalanine iso-butyl ester (prepared following General Procedure BJ above),the title compound was prepared. The reaction was monitored by tlc onsilica gel and purification was by filtration as described in thegeneral procedure.

[3500] NMR data was as follows:

[3501]¹H-nmr (CDCl₃): δ=7.47 (m, 5H), 4.66 (m, 1H), 4.16 (s, 2H), 3.91(m, 2H), 1.93 (m, 1H), 1.48 (d, 3H) 0.93 (d, 6H).

[3502] C₁₇H₂₁N₃O₃S (MW=347, Mass Spectroscopy (MH⁺348)).

Example B56 Synthesis of N-[-phenyloxazol-4-yl)acetyl]alanine iso-butylester

[3503] Following General Procedure BI above, and using(2-phenyloxazol-4-yl)acetic acid (CAS# 22086-89-1) and alanine iso-butylester (prepared following General Procedure BJ above), the titlecompound was prepared. The reaction was monitored by tlc on silica geland purification was by filtration as described in the generalprocedure.

Example B57 Synthesis of N-[(3-methylphenyl)acetyl]alanine iso-butylester

[3504] Following General Procedure BI above, and using3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3505] NMR data was as follows:

[3506]¹H-nmr (CDCl₃): δ=7.21 (m, 1H), 7.07 (m, 3H), 4.54 (m, 1H), 3.83(m, 2H), 3.52 (s, 2H), 2.35 (s, 3H), 1.87 (m, 1H), 1.32 (d, 3H), 0.88(d, 6H).

[3507] C₁₆H₂₃NO₃ (MW=277, Mass Spectroscopy (MH⁺278)).

Example B58 Synthesis of N-[(2,5-difluorophenyl)acetyl]alanine iso-butylester

[3508] Following General Procedure BI above, and using2,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3509] NMR data was as follows: ¹H-nmr (CDCl₃): δ=7.08-6.94 (m, 3H),4.57 (m, 1H), 3.91 (m, 2H), 3.56 (s, 2H), 1.92 (m, 1H), 1.41 (d, 3H)0.91 (d, 6H).

[3510] C₁₅H₁₉NO₃F₂ (MW=299, Mass Spectroscopy (MH⁺300)).

Example B59 Synthesis of N-[(3,5-diflurophenyl)acetyl]alanine iso-butylester

[3511] Following General Procedure BI above, and using3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3512] NMR data was as follows:

[3513]¹H-nmr (CDCl,): δ=6.81 (m, 2H), 6.74 (m, 1H), 6.06 (m, 1H), 4.57(m, 1H), 3.92 (m, 2H), 3.51 (s, 2H), 1.94 (m, 1H), 1.36 (d, 3H) 0.87 (d,6H).

[3514] C₁₅H₁₉NO₃F₂ (MW=299, Mass Spectroscopy (MH⁺300)).

Example B60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester

[3515] Following General Procedure BI above, and using 3-thiopheneaceticacid (Aldrich) and alanine iso-butyl ester (prepared following GeneralProcedure BJ above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by filtration asdescribed in the general procedure.

[3516] NMR data was as follows:

[3517]¹H-nmr (CDCl₃): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09(m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37(d, 3H) 0.92 (d, 6H).

[3518] Optical Rotation: [α9 ₂₃ −52 (c 1 MeOH) @ 589 nm.

[3519] C₁₃H₁₉NO₃S (MW=269, Mass Spectroscopy (MH⁺269)).

Example B61 Synthesis of N-[(4-methylphenyl)acetyl]-L-alanine iso-butylester

[3520] Following General Procedure BI above, and using4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[3521] NMR data was as follows:

[3522]¹H-nmr (CDCl₃): δ=7.11 (s, 4H), 5.93 (m, 1H), 4.58 (m, 1H), 3.88(m, 2H), 3.54 (s, 2H), 2.33 (s, 3H), 1.89 (m, 1H), 1.32 (d, 3H), 0.89(d, 6H).

[3523] C₁₆H₂₃NO₃ (MW=277.35, Mass Spectroscopy (MH⁺278)).

Example B62 Synthesis of N-(phenylacetyl)-L-alanineS-1-(methoxycarbonyl) iso-butyl ester

[3524] Following General Procedure BK and using(S)-(+)-2-hydroxy-2-methylbutyric acid (Aldrich) in place of the aminoacid, methyl (S)-(+)-2-hydroxy-2-methylbutyrate was prepared.

[3525] Methyl (S)-(+)-2-hydroxy-2-methylbutyrate was then coupled withcarbobenzyloxy-L-alanine (Aldrich) using General Procedure BE to providecarbobenzyloxy-L-alanine S-1-(methoxycarbonyl) iso-butyl ester.

[3526] Carbobenzyloxy-L-alanine S-1-(methoxycarbonyl) iso-butyl ester(1.0 g) was then dissolved in 20 mL of methanol and 6N HCl (0.5 mL) and10% palladium on carbon (0.1 g) were added. This reaction mixture washydrogenated at 40 psi of hydrogen on a Parr apparatus for 5 hours atroom temperature and then filtered through a pad of Celite. The filtratewas concentrated at reduced pressure to provide L-alanineS-1-(methoxycarbonyl) iso-butyl ester hydrochloride (98% yield).

[3527] L-Alanine S-1-(methoxycarbonyl) iso-butyl ester hydrochloride wasthen coupled to phenylacetic acid using General Procedure BG to providethe title compound.

[3528] NMR data was as follows:

[3529]¹H-nmr (CDCl₃): δ=7.35-7.20 (m, 5H), 6.22 (bd, 1H), 4.83 (d, 1H),4.65 (p, 1H), 3.68 (s, 3H), 3.55 (s, 2H), 2.21 (m, 1H), 1.40 (d, 3H),0.97 (d, 3H), 0.93 (d, 3H).

[3530]¹³C-nmr (CDCl₃): δ=173.25, 171.18, 170.22, 135.11, 129.94, 129.50,127.88, 52.67, 48.49, 43.98, 30.53, 19.21, 18.75, 17.58.

Example B63 Synthesis of N-[(3-nitrophenyl)acetyl]-L-alanine iso-butylester

[3531] Following General Procedure BH above and using3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl esterhydrochloride (from Example BB above), the title compound was prepared.The reaction was monitored by tlc on silica gel and purification was byrecrystallization from butyl chloride.

[3532] NMR data was as follows:

[3533]¹H-nmr (CDCl₃): δ=8.17 (m, 2H), 7.68 (d, 1H), 7.52 (t, 1H), 6.18(m, 1H), 4.48 (m, 1H), 3.94 (m, 2H), 3.67 (s, 2H), 1.93 (m, 1H), 1.42(d, 3H), 0.91 (d, 3H).

[3534] Optical Rotation: [α]₂₃ −49 (c 5, MeOH).

Example B64 Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethylester

[3535] Following General Procedure BG and using 3,5-difluorophenylaceticacid (Aldrich) and alanine ethyl ester (Aldrich), the title compound wasprepared as a solid with a melting. point of 93°-95° C. The reaction wasmonitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was bychromatography on silica gel using EtOAc as the eluant followed byrecrystallization from 1-chlorobutane.

[3536] NMR data was as follows: ¹H-nmr (DMSO-d₆): δ=1.30 (d, 3H); 3.52(s, 2H).

[3537] C₁₃H₁₅NO₃F₂ (MW=271.26, Mass Spectroscopy (MH⁺271)).

Example B65 Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester

[3538] Following General Procedure BG above and using3-nitrophenylacetic acid (Aldrich) and methionine ethyl esterhydrochloride (Aldrich), the title compound was prepared. The reactionwas monitored by tlc on silica gel and purification was byrecrystallization from butyl chloride.

[3539] NMR data was as follows:

[3540]¹H-nmr (CDCl₃): δ=8.18 (s, 1H), 8.15 (d, 1H) 7.66 (d, 1H), 7.48(t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47(t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H).

[3541] Optical Rotation: [α]₂₃ −30 (c 5, MeOH).

Example B66 Synthesis of N-[(3-chlorophenyl)acetyl]alanine iso-butylester

[3542] Following General Procedure BG above and using3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester(prepared following General Procedure BJ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel.

[3543] NMR data was as follows:

[3544]¹H-nmr (CDCl₃): δ=7.29 (m, 3H), 7.18 (m, 1H), 6.0 (m, 1H), 4.56(m, 1H), 3.89 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.39 (d, 3H), 0.91(d, 3H).

[3545] Optical Rotation: [α]₂₃ −45 (c 5, MeOH).

[3546] C₁₅H₂₀NO₃Cl (MW=297.78, Mass Spectroscopy (MH⁺297)).

Example B67 Synthesis of N-[(3-chlorophenyl)acetyl]alanine2-(NN-dimethylamino)ethyl ester

[3547] Following General Procedure BC above, and usingN-(3-chlorophenyl-acetyl)alanine (from Example BD above) and2-(N,N-dimethyl amino) ethanol (Aldrich), the title compound can beprepared. The reaction was monitored by tic on silica gel andpurification was by liquid chromatography using 0.1:2:0.79NH₄OH:EtOH:CHCl₃ as the eluant.

[3548] NMR data was as follows:

[3549]¹H-nmr (CDCl₃): 7.37 (s, 1H), 7.33-7.2 (m, 3H), 4.675-4.6 (m, 1H),4.5-4.37 (m, 1H), 4.25-4.13 (m, 1H), 3.6 (d, J=7 Hz, 2H), 2.86 (bs, 2H),2.3 (s, 6H), 1.23 (d, J=9 Hz, 3H).

[3550] C₁₅H₁₂N₂O₃Cl (MW=313.799, Mass Spectroscopy (M⁺313)).

Example B68 Synthesis of 2-[(3,5-dichlorophenyl)acetamido]hexanoic acidmethyl ester

[3551] Following General Procedure BF above, an using3,5-dichlorophenylacetic acid (from Example BC above) and L-norleucinemethyl ester hydrochloride (Bachem), the title compound was prepared asa solid having a melting point of 77°-78° C. The reaction was monitoredby tlc on silica gel (Rf=0.70 in 40% EtOAC/hexanes) and purification wasby flash chromatography on silica gel using 40% EtOAc/hexanes as theeluant.

[3552] NMR data was as follows:

[3553]¹H-nmr (CDCl₃): δ=7.20 (s), 7.18 (s), 6.6 (m), 4.55 (m), 3.7 (s),3.5 (s), 3.4 (s), 2.0 (s), 1.8 (m), 1.6 (m), 1.2 (m), 0.8 (t).

[3554]¹³C-nmr (CDCl₃): δ=173.54, 169.67, 138.43, 135.72, 128.33, 128.07,78.04, 77.62, 77.19, 53.04, 52.90, 43.14, 32.57, 27.87, 22.81, 14.41.

Example B69 Synthesis of N-[(3,5-diclorophenyl)acetyl]-L-alanineiso-butyl ester

[3555] Following General Procedure BF above, and using3,5-dichlorophenylacetic - acid (from Example BC above) and L-alanineiso-butyl ester hydrochloride (from Example BB above), the titlecompound was prepared as a solid having a melting point of 115°-116° C.The reaction was monitored by tlc on silica gel (Rf=0.40 in 3%methanol/dichloromethane) and purification was by flash chromatographyon silica gel using 3% methanol/dichloromethane as the eluant.

[3556] NMR data was as follows:

[3557]¹H-nmr (CDCl₃): δ=7.27 (d, J=2 Hz, 1H), 7.19 (s, 2H), 6.22 (d, J=6Hz, 1H), 4.59 (quint., J=7 Hz, 1H), 3.9 (q, J=4 Hz, 2H), 3.5 (s, 2H),1.9 (m, 1H), 1.4 (d, J=7 Hz, 3H), 0.91 (d, J=7 Hz, 6H).

[3558]¹³C-nmr (CDCl₃): δ=173.45, 169.37, 138.31, 135.75, 128.39, 128.11,78.04, 77.61, 77.19, 72.19, 54.03, 48.97, 43.12, 28.24, 19.52, 19.49,19.09.

[3559] C₁₅H₁₉NO₃Cl₂ (MW=331.9, Mass Spectroscopy (MH⁺332)).

Example B70 Synthesis of N-(cyclohexylacetyl)-L-alanine iso-butyl ester

[3560] Following General Procedure BB above, and using cyclohexylaceticacid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from ExampleBB above), the title compound was prepared as a solid having a meltingpoint of 92° C.-93° C. The reaction was monitored by tlc on silica gel(Rf=0.39 in 1:3 EtOAc:hexane) and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[3561] NMR data was as follows:

[3562] 1H-nmr (CDCl₃): δ=0.93 (d, J.=6.7 Hz, 6H), 0.85-1.01 (m, 2H),1.05-1.35 (m, 3H), 1.40 (d, J=7.1 Hz, 3H), 1.60-1.85 (m, 6H), 1.95 (m,1H), 2.06 (d, J=7.0 Hz, 2H), 3.92 (m, 2H), 4.61 (m, 1H), 6.08 (bd, 1H).

[3563]¹³C-nmr (CDCl₃): δ=18.7, 18.9, 26.0, 26.1, 27.6, 33.0, 35.3, 44.6,47.9, 71.4, 171.8, 173.3.

[3564] C₁₅H₂₇NO₃ (MW=269.39, Mass Spectroscopy (MH⁺270)).

Example B71 Synthesis of N-(cyclopentylacetyl)-L-alanine iso-butyl ester

[3565] Following General Procedure BB above, and using cyclopentylaceticacid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from ExampleBB above), the title compound was prepared as a solid having a meltingpoint of 62° C.-64° C. The reaction was monitored by tlc on silica gel(Rf=0.37 in 1:3 EtOAc:hexane) and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[3566] NMR data was as follows:

[3567]¹H-nmr (CDCl₃): δ=0.87 (d, J=6.8 Hz, 6H), 1.01-1.17 (m, 2H), 1.34(d, J=7.2 Hz, 3H), 1.40-1.62 (m, 4H), 1.70-1.83 (m, 2H), 1.89 (m, 1H),2.15 (m, 3H), 3.86 (m, 2H), 4.55 (m, 1H), 6.30 (d, J=7.1 Hz, 1H).

[3568]¹³C-nmr (CDCl₃): δ=18.4, 18.78, 18.80, 24.8 (very high), 27.5,32.27, 32.32,36.9, 42.5, 47.7, 71.2, 172.2, 173.2.

[3569] Elemental Analysis-Calc (%): C, 65.85;H, 9.87; N. 5.49; Found(%): C, 66.01;H, 10.08; N, 5.49.

[3570] C₁₄H₂₅NO₃ (MW=255.36, Mass Spectroscopy (MH⁺256)).

Example B72 Synthesis of N-[(cyclohex-1-enyl)acetyl]-L-alanine iso-butylester

[3571] Following General Procedure BB above, and using cyclohex-1-enylacetic acid (Alfa) and L-alanine iso-butyl ester hydrochloride (fromExample BB above), the title compound was prepared as a solid having amelting point of 49° C.-51° C. The reaction was monitored by tlc onsilica gel (Rf=0.40 in 1:3 EtOAc:hexane) and purification was byextraction with Et₂O followed by washes with aqueous K₂CO₃ and aqueousHCl.

[3572] NMR data was as follows:

[3573]¹H-nmr (CDCl₃): δ=0.91 (d, J=4.5 Hz, 3H), 0.93 (d, J=6.7 Hz, 3H),1.40 (d, J=7.2 Hz, 3H), 1.52-1.70 (m, 4H), 1.97 (m, 3H), 2.06 (bs, 2H),2.89 (s, 2H), 3.92 (m, 2H), 4.59 (m, 1H), 5.65 (s, 1H), 6.33 (d, J=6.6Hz, 1H).

[3574]¹³C-nmr (CDCl₃): δ=18.7, 18.91, 18.93, 21.9, 22.7, 25.3, 27.6,28.3, 46.1, 47.9, 71.4, 127.1, 132.5, 170.6, 173.1.

[3575] Elemental Analysis-Calc (%): C, 67.38;H, 9.42; N, 5.24; Found(%): C, 67.34;H, 9.54; N, 5.16.

[3576] C₁₅H₂₅NO₃ (MW=267.37, Mass Spectroscopy (MH⁺268)).

Example B73 Synthesis of N-[(3-chlorophenyl)acetyl]alanine3-methylbut-2-enyl thioester

[3577] Following General Procedure BC above, and usingN-[(3-chlorophenyl)acetyl]alanine and 3-methyl-2-butene thioester (TCI),the title compound can be prepared. The reaction was monitored by tlc onsilica gel and purification was by liquid chromatography using 3:7EtOAc:Hexane as the eluant.

[3578] NMR data was as follows:

[3579]¹H-nmr (DMSO-d₆): δ=5.2-5.075 (m, 1H), 4.37 (dq, J=9 Hz, 1H), 3.56(s), 3.43 (d, J=12 Hz. 2H), 1.266 (d, J=12 Hz, 6H) 1.3 (d, J=9 Hz, 3H).

[3580] C₁₆H₂₀NO₂ClS (MW=325.86, Mass Spectroscopy (M⁺325)).

Example B74 Synthesis of N-[(2-phenyl)-2-fluoroacetyl]alanine ethylester

[3581] Following General Procedure BF above, and using α-fluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc on silica gel(Rf=0.75 in 1:1 EtOAc:hexane) and purification was by chromatography onsilica gel using 1:2 ethyl acetate/hexanes as the eluent.

[3582] NMR data was as follows:

[3583]¹H-nmr (DMSO-d₆): δ=1.14 (q, 3H), 1.34 (d, 3H), 4.07 (m, 2H), 4.33(m, 1H), 5.84 (d, 1H), 6.01 (d, 1H), 7.40-7.55 (m, 5H), 8.87 (m, 1H).

[3584] C₁₃H₁₆NO₃F (MW=253.27, Mass Spectroscopy (MH⁺253)).

Example B75 Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycinemethyl ester

[3585] Following General Procedure BF above, and using3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycine methyl esterhydrochloride (Bachem), the title compound was prepared.

[3586] NMR data was as follows: ¹H-nmr (CDCl₃): δ=7.4-7.3 (m, 5H),6.9-6.7 (m, 3H), 6.55 (d 1H, 7.1 Hz), 5.56 (d 1H 7 Hz), 3.72 (s 3H),3.57 (s 2H)

[3587]¹³C-nmr (CDCl₃): δ=197.6, 177.6, 171.8, 169.3, 136.7, 129.6,129.3, 127.8, 113.0, 112.9, 112.7, 111.4, 103.8, 103.5, 65.1, 57.2,53.5, 45.1, 43.3, 43.3

[3588] C₁₇H₁₅NO₃F₂ (MW=319.31, Mass Spectroscopy (MH+320)).

Example B76 Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycineiso-butyl ester

[3589] The 3,5-difluorophenylacetic acid (Aldrich) was EDC coupled toL-phenylglycine methyl ester hydrochloride (Bachem) via GeneralProcedure BF above.

[3590] The resulting compound was placed in a large excess of thedesired alcohol. A catalytic amount of dry NaH was added, and thereaction was followed by tlc until the presence of starting material wasno longer detected. The reaction was quenched with a few milliliters ofIN HCl, and after a few minutes of stirring saturated aqueous NaHCO₃ wasadded. The volume of the reaction mixture was reduced on a rotaryevaporator until the excess alcohol was removed and then the remainingresidue was taken up in ethyl acetate and additional water was added.The organic phase was washed with saturated aqueous NaCl and dried overMgSO₄. The solution was stripped free of solvent on a rotary evaporator,and the crude product residue was then further purified bychromatography.

[3591] NMR data was as follows:

[3592] 1H-nmr (CDCl₃): δ=7.35-7.3 (m 5H), 6.8-6.7 (m 3H) 6.60 (d 1H,7Hz), 5.55 (d 1H 7.1 Hz), 3.9 (m 2H), 3.60 (s 2H), 1.85 (m 1H 7 Hz), 0.8(q 6H 7 Hz)

[3593]¹³C-nmr (CDCl₃): δ=171.3, 169.3, 165.4, 138.5, 137.0, 129.5,129.2, 127.6, 113.1, 113.0, 112.8, 112.7, 103.8, 103.5, 103.2, 75.5,57.2, 43.4, 43.3, 28.2, 19.3

[3594] C₂₀H₂₁NO₃F₂ (MW=361.39, Mass Spectroscopy (MH⁺362)).

Example B77 Synthesis of N-(cyclopentylacetyl)-L-phenylglycine methylester

[3595] Following General Procedure BD above, and using cyclopentylaceticacid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem)the title compound was prepared.

[3596] NMR data was as follows:

[3597] 1H-nmr (CDCl₃): δ=7.35 (s, 5H), 6.44 (bd, 1H), 5.6 (d, 1H), 3.72(s, 3H), 2.24 (bs, 3H), 1.9-1.4 (m, 6H), 1.2-1.05 (m, 2H)

[3598]¹³C-nmr (CDCl₃): δ=172.3, 171.7, 136.7, 129.0, 128.6, 127.3, 56.2,52.7, 42.5, 36.9, 32.40, 32.38, 24.8

Example B78 Synthesis of N-(cyclopentylacetyl)-L-alanine methyl ester

[3599] Following General Procedure BD above, and using cyclopentylaceticacid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma) thetitle compound was prepared.

[3600] NMR data was as follows:

[3601]¹H-nmr (CDCl₃): δ=6.38 (d, 1H), 4.50 (m, 1H), 3.65 (s, 3H), 2.13(bs, 3H), 1.80-1.00 (m (includes d at 1.30, 3H), 11H)

[3602]¹³C-nmr (CDCl₃): δ=173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15,32.14, 18.0

[3603] C₁₁H₁₉NO₃ (MW=213.28, Mass Spectroscopy (MH⁺214)).

Example B79 Synthesis of N-(cyclopropylacetyl)-L-phenylglycine methylester

[3604] Following General Procedure BD above, and using cyclopropylaceticacid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem),the title compound was prepared.

[3605] NMR data was as follows:

[3606]¹H-nmr (CDCl₃): δ=7.35 (m, 5H) 6.97 (bd, J=7.2 Hz, 1H) 5.59 (d,J=7.8 Hz, 1H), 3.71 (s, 3H), 2.17 (m, 2H), 1.05-0.95 (m, 1H), 0.62 (m,2H), 0.02 (m, 2H)

[3607]¹³C-nmr (CDCl₃): δ=171.9, 174.6, 136.6, 129.0, 128.5, 127.2, 56.1,52.7, 41.0, 6.9, 4.37, 4.33

Example B80 Synthesis of N-(cyclopropylacetyl)-L-alanine methyl ester

[3608] Following General Procedure BD above, and using cyclopropylaceticacid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), thetitle compound was prepared.

[3609] NMR data was as follows:

[3610]¹H-nmr (CDCl₃): δ=6.60 (d, 1H), 4.55 (m, 1H), 3.69 (s, 3H), 2.10(m, 2H), 1:34 (d, 3H), 0.95 (m, 1H), 0.58 (m, 2H) 0.15 (m, 2H)

[3611]¹³C-nmr (CDCl₃): δ=173.7, 172.3, 52.3, 47.7, 41.0, 18.2, 6.7,4.27, 4.22

Example B81 Synthesis of N-[(3-nitrophenyl)acetyl]-L-methionineiso-butyl ester

[3612] Following General Procedure BH above, and using nitrophenylaceticacid (Aldrich) and L-methionine (Aldrich), the title compound wasprepared as a tan oil. The reaction was monitored by tlc on silica gel.

[3613] NMR data was as follows: ¹H-nmr (CDCl₃): δ=8.16 (m,2H) 7.67(d,1H) 7.32 (t, 1H), 6.31 (bd, 1H), 4.69 (m, 1H), 3.90 (d, 2H), 3.68 (s,2H), 2.47 (t, 2H), 2.15 (m, 1H), 2.02 (s, 3H), 1.90 (m, 2H), 0.91 (d,6H).

[3614] C₁₇H₂₄N₂O₅S (MW=368.4, Mass Spectroscopy (MH⁺368)).

[3615] Additionally, each of the carboxylic acids described above (orthe carboxylic acids prepared by hydrolysis of the above carboxylic acidesters) could be coupled with an appropriate α-aminolactam to providefor compounds of the formula:

[3616] where R¹—[Z]_(m)—NH—CHR²—C(O)— is the residue of the carboxylicacid (i.e., R¹, R², Z, and m are as defined above) and W″ is selectedfrom the following structures:

Example Bio-1 Cellular Screen for the Detection of Inhibitors ofβ-Amyloid Production

[3617] Numerous compounds of formula I above were assayed for theirability to inhibit β-amyloid production in a cell line possessing theSwedish mutation. This screening assay employed cells (K293=human kidneycell line) which were stably transfected with the gene for amyloidprecursor protein 751 (APP751) containing the double mutationLys₆₅₁Met₆₅₂ to Asn₆₅₁Leu₆₅₂ (APP751 numbering) in the manner describedin International Patent Application Publication No. 94/10569⁸ and Citronet al.¹². This mutation is commonly called the Swedish mutation and thecells, designated as “293 751 SWE”, were plated in Corning 96-wellplates at 2-4×10⁴ cells per well in Dulbecco's minimal essential media(Sigma, St. Louis, Mo.) plus 10% fetal bovine serum. Cell number isimportant in order to achieve β-amyloid ELISA results within the linearrange of the assay (˜0.2 to 2.5 ng per mL).

[3618] Following overnight incubation at 37° C. in an incubatorequilibrated with 10% carbon dioxide, media were removed and replacedwith 200 μL of a compound of formula I (drug) containing media per wellfor a two hour pretreatment period and cells were incubated as above.Drug stocks were prepared in 100% dimethyl sulfoxide such that at thefinal drug concentration used in the treatment, the concentration ofdimethyl sulfoxide did not exceed 0.5% and, in fact, usually equaled0.1%.

[3619] At the end of the pretreatment period, the media were againremoved and replaced with fresh drug containing media as above and cellswere incubated for an additional two hours. After treatment, plates werecentrifuged in a Beckman GPR at 1200 rpm for five minutes at roomtemperature to pellet cellular debris from the conditioned media. Fromeach well, 100 μL of conditioned media or appropriate dilutions thereofwere transferred into an ELISA plate precoated with antibody 266 [P.Seubert, Nature (1992) 359:325-327]against amino acids 13-28 ofβ-amyloid peptide as described in International Patent ApplicationPublication No. 94/10569⁸ and stored at 4° C. overnight. An ELISA assayemploying labelled antibody 3D6 [P. Seubert, Nature (1992)359:325-327]against amino acids 1-5 of β-amyloid peptide was run thenext day to measure the amount of β-amyloid peptide produced.

[3620] Cytotoxic effects of the compounds were measured by amodification of the method of Hansen, et al.¹³. To the cells remainingin the tissue culture plate was added 25 μL of a3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)(Sigma, St. Louis, Mo.) stock solution (5 mg/nL) to a finalconcentration of 1 mg/mL. Cells were incubated at 37° C. for one hour,and cellular activity was stopped by the addition of an equal volume ofMTT lysis buffer (20% w/v sodium dodecylsulfate in 50%dimethylformamide, pH 4.7). Complete extraction was achieved byovernight shaking at room temperature. The difference in the OD_(562nm)and the OD_(650nm) was measured in a Molecular Device's UV_(max)microplate reader as an indicator of the cellular viability.

[3621] The results of the β-amyloid peptide ELISA were fit to a standardcurve and expressed as ng/mL β-amyloid peptide. In order to normalizefor cytotoxicity, these results were divided by the MTT results andexpressed as a percentage of the results from a drug free control. Allresults are the mean and standard deviation of at least six replicateassays.

[3622] The test compounds were assayed for β-amyloid peptide productioninhibition activity in cells using this assay. The results of this assaydemonstrate that the compounds of formula I inhibit β-amyloid peptideproduction by at least 30% as compared to control.

Example Bio-2 In Vivo Suppression of β-Amyloid Release and/or Synthesis

[3623] This example illustrates how the compounds of this inventioncould be tested for in vivo suppression of β-amyloid release and/orsynthesis. For these experiments, 3 to 4 month old PDAPP mice are used[Games et al., (1995) Nature 373:523-527]. Depending upon which compoundis being tested, the compound is usually formulated at between 1 and 10mg/mL. Because of the low solubility factors of the compounds, they maybe formulated with various vehicles, such as corn oil (Safeway, SouthSan Francisco, Calif.); 10% ethanol in corn oil;2-hydroxypropyl-β-cyclodextrin (Research Biochemicals International,Natick Mass.); and carboxy-methyl-cellulose (Sigma Chemical Co., St.Louis Mo.).

[3624] The mice are dosed subcutaneously with a 26 gauge needle and 3hours later the animals are euthanized via CO₂ narcosis and blood istaken by cardiac puncture using a 1 cc 25G ⅝″ tuberculin syringe/needlecoated with solution of 0.5 M EDTA, pH 8.0. The blood is placed in aBecton-Dickinson vacutainer tube containing EDTA and spun down for 15minutes at 1500×g at 5° C. The brains of the mice are then removed andthe cortex and hippocampus are dissected out and placed on ice.

[3625] 1. Brain Assay

[3626] To prepare hippocampal and cortical tissue for enzyme-linkedimmunosorbent assays (ELISAs) each brain region is homogenized in 10volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 mMTris-HCl, pH 8.0) using a Kontes motorized pestle (Fisher, PittsburghPa.). The homogenates are gently rocked on a rotating platform for threeto four hours at room temperature and stored at −20° C. prior toquantitation of β-amyloid.

[3627] The brain homogenates are diluted 1:10 with ice-cold caseinbuffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodiumazide, 20 μg/ml aprotinin, 5 mM EDTA, pH 8.0, 10 μg/ml leupeptin],thereby reducing the final concentration of guanidine to 0.5 M, beforecentrifugation at 16,000×g for 20 minutes at 4° C. Samples are furtherdiluted, if necessary, to achieve an optimal range for the ELISAmeasurements by the addition of casein buffer with 0.5 M guanidinehydrochloride added. The β-amyloid standards (140 or 142 amino acids)were prepared such that the final composition equaled 0.5 M guanidine inthe presence of 0.1% bovine serum albumin (BSA).

[3628] The total β-amyloid sandwich ELISA, quantitating both β-amyloid(aa 1-40) and β-amyloid (aa 1-42) consists of two monoclonal antibodies(mAb) to β-amyloid. The capture antibody, 266 [P. Seubert, Nature (1992)359:325-327], is specific to amino acids 13-28 of β-amyloid. Theantibody 3D6 [Johnson-Wood et al., PNAS USA (1997) 94:1550-1555], whichis specific to amino acids 1-5 of β-amyloid, is biotinylated and servedas the reporter antibody in the assay. The 3D6 biotinylation procedureemploys the manufacturer's (Pierce, Rockford Ill.) protocol forNHS-biotin labeling of immunoglobulins except that 100 mM sodiumbicarbonate, pH 8.5 buffer is used. The 3D6 antibody does not recognizesecreted amyloid precursor protein (APP) or full-length APP but detectsonly β-amyloid species with an amino terminal aspartic acid. The assayhas a lower limit of sensitivity of ˜50 pg/ml (11 pM) and shows nocross-reactivity to the endogenous murine β-amyloid peptide atconcentrations up to 1 ng/ml.

[3629] The configuration of the sandwich ELISA quantitating the level ofβ-amyloid (aa 1-42) employs the mAb 21F12 [Johnson-Wood et al., PNAS USA(1997) 94:1550-1555](which recognizes amino acids 33-42 of β-amyloid) asthe capture antibody. Biotinylated 3D6 is also the reporter antibody inthis assay which has a lower limit of sensitivity of ˜125 pg/ml (28 pM).

[3630] The 266 and 21F12 capture mAbs are coated at 10 μg/ml into 96well immunoassay plates (Costar, Cambidge Mass.) overnight at roomtemperature. The plates are then aspirated and blocked with 0.25% humanserum albumin in PBS buffer for at least 1 hour at room temperature,then stored desiccated at 4° C. until use. The plates are rehydratedwith wash buffer (Tris-buffered saline, 0.05% Tween 20) prior to use.The samples and standards are added to the plates and incubatedovernight at 4° C. The plates are washed ≧3 times with wash bufferbetween each step of the assay. The biotinylated 3D6, diluted to 0.5μg/ml in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH7.4) is incubated in the well for 1 hour at room temperature. Avidin-HRP(Vector, Burlingame Calif.) diluted 1:4000 in casein incubation bufferis added to the wells for 1 hour at room temperature. The colorimetricsubstrate, Slow TMB-ELISA (Pierce, Cambridge Mass.), is added andallowed to react for 15 minutes, after which the enzymatic reaction isstopped with addition of 2 N H₂SO₄. Reaction product is quantified usinga Molecular Devices Vmax (Molecular Devices, Menlo Park Calif.)measuring the difference in absorbance at 450 nm and 650 nm.

[3631] 2. Blood Assay

[3632] The EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/lsodium phosphate-H₂O (monobasic), 2.16 gm/l sodium phosphate-7H₂O(dibasic), 0.5 gm/l thimerosal, 8.5 gm/l sodium chloride, 0.5 ml TritonX-405, 6.0 g/l globulin-free bovine serum albumin; and water). Thesamples and standards in specimen diluent are assayed using the totalβ-amyloid assay (266 capture/3D6 reporter) described above for the brainassay except the specimen diluent was used instead of the caseindiluents described.

[3633] Formulations other than those described above can also be usedfor oral delivery and intravenous delivery to a mammal. For oraldelivery, the compound can be mixed with either 100% corn oil or,alternatively, in a solution containing 80% corn oil, 19.5% oleic acidand 0.5% labrafil. The compound can be mixed with the above solutions inconcentrations ranging from 1 mg/mL to 10 mg/mL. The compound insolution is preferably administered orally to the mammal at a dosevolume of 5 mL/kg of body weight. For IV delivery, the compound ispreferably mixed with a solution of 3% ethanol, 3% solutol HS-15 and 94%saline. The compound is preferably mixed with the above solution inconcentrations ranging from 0.25 mg/mL to 5 mg/mL. The compound insolution is preferably administered by IV to the mammal at a dose volumeof 2 mL/kg of body weight.

[3634] From the foregoing description, various modifications and changesin the composition and method will occur to those skilled in the art.All such modifications coming within the scope of the appended claimsare intended to be included therein.

What is claimed is:
 1. A method for inhibiting β-amyloid peptide releaseand/or its synthesis in a cell which method comprises administering tosuch a cell an amount of a compound or a mixture of compounds effectivein inhibiting the cellular release and/or synthesis of β-amyloid peptidewherein said compounds are represented by formula I:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with—C(H)_(p)C(═X)—, forms a cycloalkyl, cycloalkenyl, heterocyclic,substituted cycloalkyl, or substituted cycloalkenyl group wherein eachof said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkylor substituted cycloalkenyl group is optionally fused to form a bi- ormulti-fused ring system (preferably no more than 5 fused rings) with oneor more ring structures selected from the group consisting ofcycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which,in turn, each of such ring structures are optionally substituted with 1to 4 substituents selected from the group consisting of hydroxyl, halo,alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro,cyano, carboxyl, carboxyl esters, alky, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino,N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substitutedalkylamino, N,N-disubstituted alkylamino, —NHC(O)R⁴, —NHSO₂R⁴, —C(O)NH₂,—C(O)NHR⁴, —C(O)NR⁴R⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NHR⁴ and —S(O)₂NR⁴R⁴where each R⁴ is independently selected from the group consisting ofalkyl, substituted alkyl, or aryl; X is selected from the groupconsisting of oxo (═O), thiooxo (═S), hydroxyl (—H, —OH), thiol (H,—SH)and hydro (H,H); Y is represented by the formula:

wherein each R² is independently selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Z isrepresented by the formula —T—CX′X″C(O)— where T is selected from thegroup consisting of a bond covalently linking R¹ to —CX′X″—, oxygen,sulfur, —NR⁵ where R⁵ is hydrogen, acyl, alkyl, aryl or heteroarylgroup; X′ is hydrogen, hydroxy or fluoro, X″ is hydrogen, hydroxy orfluoro, or X′ and X″ together form an oxo group; m is an integer equalto 0 or 1; n is an integer equal to 0, 1 or 2; p is an integer equal to0 or 1 such that when p is zero, the ring defined by W and—C(H)_(p)C(═X)— is unsaturated at the carbon atom of ring attachment toY and when p is one, the ring is saturated at the carbon atom of ringattachment to Y, with the following provisos: A. when R¹ is3,5-difluorophenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is1, then W, together with >CH and >C═X, does not form a 2-(S)-indanolgroup; B. when R¹ is phenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form atrans-2-hydroxy-cyclohex-1-yl group; C. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a gammabutyrolactone group or a5,5-dimethyl-gammabutyrolactone group; D. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a ε-caprolactam group; E. when R¹ iscyclopropyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an N-methylcaprolactamgroup; F. when R¹ is 4-chlorobenzoyl-CH₂—, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform an 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G.when R¹ is 2-phenylphenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form an7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R¹ isCH₃OC(O)CH₂—, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an2,3-dihydro-1-(t-butylC(O)CH₂-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;I. when R¹ is 4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,CH₃OC(O)CH₂—, 4-HOCH₂-phenyl, 2,4,6-trifluorophenyl,2-trifluoromethyl-4-fluorophenyl, or CH₃S—, R² is —CH₃, Z is —CH₂C(O)—,m is 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;J. when R¹ is 2,6-difluorophenyl, R² is —CH₃, Z is —CH(OH)C(O)—, m is 1,n is 1, and p is 1, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,K. when m is 1 and n is 1, then

 does not equal cycloalkyl of from 3 to 8 carbon atoms optionallysubstituted with 1 to 3 alkyl groups.
 2. A method for preventing theonset of AD in a human patient at risk for developing AD which methodcomprises administering to said patient a pharmaceutical compositioncomprising a pharmaceutically inert carrier and an effective amount of acompound or a mixture of compounds of formula I:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with—C(H)_(p)C(═X)—, forms a cycloalkyl, cycloalkenyl, heterocyclic,substituted cycloalkyl, or substituted cycloalkenyl group wherein eachof said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkylor substituted cycloalkenyl group is optionally fused to form a bi- ormulti-fused ring system (preferably no more than 5 fused rings) with oneor more ring structures selected from the group consisting ofcycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which,in turn, each of such ring structures are optionally substituted with 1to 4 substituents selected from the group consisting of hydroxyl, halo,alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro,cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino,N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substitutedalkylamino, N,N-disubstituted alkylamino, —NHC(O)R⁴, —NHSO₂R⁴, —C(O)NH₂,—C(O)NHR⁴, —C(O)NR⁴R⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NHR⁴ and —S(O)₂NR⁴R⁴where each R⁴ is independently selected from the group consisting ofalkyl, substituted alkyl, or aryl; X is selected from the groupconsisting of oxo (═O), thiooxo (═S), hydroxyl (—H, —OH), thiol (H,—SH)and hydro (H,H); Y is represented by the formula:

wherein each R² is independently selected from the group consisting ofalkyl substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Z isrepresented by the formula —T—CX′X″C(O)— where T is selected from thegroup consisting of a bond covalently linking R¹ to —CX′X″—, oxygen,sulfur, —NR⁵ where R⁵ is hydrogen, acyl, alkyl, aryl or heteroarylgroup; X′ is hydrogen, hydroxy or fluoro, X″ is hydrogen, hydroxy orfluoro, or X′ and X″ together form an oxo group; m is an integer equalto 0 or 1; n is an integer equal to 0, 1 or 2; p is an integer equal to0 or 1 such that when p is zero, the ring defined by W and—C(H)_(p)C(═X)— is unsaturated at the carbon atom of ring attachment toY and when p is one, the ring is saturated at the carbon atom of ringattachment to Y, with the following provisos: A. when R¹ is3,5-difluorophenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is1, then W, together with >CH and >C═X, does not form a 2-(S)-indanolgroup; B. when R¹ is phenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form atrans-2-hydroxy-cyclohex-1-yl group; C. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a gammabutyrolactone group or a5,5-dimethyl-gammabutyrolactone group; D. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a E-caprolactam group; E. when R¹ iscyclopropyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an N—methylcaprolactamgroup; F. when R¹ is 4chlorobenzoyl-CH₂—, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform an 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G.when R¹ is 2-phenylphenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >—CH and >C═X, does not form an7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R¹ isCH₃OC(O)CH₂—, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an2,3-dihydro-1-(t-butylC(O)CH₂-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;I. when R¹ is 4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,CH₃OC(O)CH₂—, 4-HOCH₂-phenyl, 2,4,6-trifluorophenyl,2-trifluoromethyl-4-fluorophenyl, or CH₃S—, R² is —CH₃, Z is —CH₂C(O)—,m is 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;J. when R¹ is 2,6-difluorophenyl, R² is —CH₃, Z is —CH(OH)C(O)—, m is 1,n is 1, and p is 1, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(N,N-diethylamino-CH₂CH2-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,K. when m is 1 and n is 1, then

 does not equal cycloalkyl of from 3 to 8 carbon atoms optionallysubstituted with 1 to 3 alkyl groups.
 3. A method for treating a humanpatient with AD in order to inhibit further deterioration in thecondition of that patient which method comprises administering to saidpatient a pharmaceutical composition comprising a pharmaceutically inertcarrier and an effective amount of a compound or a mixture of compoundsof formula I:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with—C(H)_(p)C(═X)—, forms a cycloalkyl, cycloalkenyl, heterocyclic,substituted cycloalkyl, or substituted cycloalkenyl group wherein eachof said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkylor substituted cycloalkenyl group is optionally fused to form a bi- ormulti-fused ring system (preferably no more than 5 fused rings) with oneor more ring structures selected from the group consisting ofcycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which,in turn, each of such ring structures are optionally substituted with 1to 4 substituents selected from the group consisting of hydroxyl, halo,alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro,cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino,N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substitutedalkylamino, N,N-disubstituted alkylamino, —NHC(O)R⁴, —NHSO₂R⁴, —C(O)NH₂,—C(O)NHR⁴, —C(O)NR⁴R⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NHR⁴ and —S(O)₂NR⁴R⁴where each R⁴ is independently selected from the group consisting ofalky, substituted alkyl, or aryl; X is selected from the groupconsisting of oxo (═O), thiooxo (═S), hydroxyl (—H, —OH), thiol (H,—SH)and hydro (H,H); Y is represented by the formula:

wherein each R² is independently selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Z isrepresented by the formula —T—CX′X″C(O)— where T is selected from thegroup consisting of a bond covalently linking R¹ to —CX′X″—, oxygen,sulfur, —NR⁵ where R⁵ is hydrogen, acyl, alkyl, aryl or heteroarylgroup; X′ is hydrogen, hydroxy or fluoro, X″ is hydrogen, hydroxy orfluoro, or X′ and X″ together form an oxo group; m is an integer equalto 0 or 1; n is an integer equal to 0, 1 or 2; p is an integer equal to0 or 1 such that when p is zero, the ring defined by W and—C(H)_(p)C(═X)— is unsaturated at the carbon atom of ring attachment toY and when p is one, the ring is saturated at the carbon atom of ringattachment to Y, with the following provisos: A. when R¹ is3,5-difluorophenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is1, then W, together with >CH and >C═X, does not form a 2-(S)-indanolgroup; B. when R¹ is phenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form atrans-2-hydroxy-cyclohex-1-yl group; C. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a gammabutyrolactone group or a5,5-dimethyl-gammabutyrolactone group; D. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a ε-caprolactam group; E. when R¹ iscyclopropyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an N-methylcaprolactamgroup; F. when R¹ is 4-chlorobenzoyl-CH₂—, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform an 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G.when R¹ is 2-phenylphenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form an7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R¹ isCH₃OC(O)CH₂—, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an2,3-dihydro-1-(t-butylC(O)CH₂-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;I. when R¹ is 4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,CH₃OC(O)CH₂—, 4-HOCH₂-phenyl, 2,4,6-trifluorophenyl,2-trifluoromethyl4-fluorophenyl, or CH₃S—, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;J. when R¹ is 2,6-difluorophenyl, R² is —CH₃, Z is —CH(OH)C(O)—, m is 1,n is 1, and p is 1, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,K. when m is 1 and n is 1, then

 does not equal cycloalkyl of from 3 to 8 carbon atoms optionallysubstituted with 1 to 3 alkyl groups.
 4. A method according to any ofclaims 1, 2 or 3 where, in formula I, m is zero.
 5. A method accordingto claim 4 wherein R¹ is aryl or heteroaryl.
 6. A method according toclaim 5 wherein R¹ is selected from the group consisting of (a) phenyl,(b) a substituted phenyl group of the formula:

wherein R^(c) is selected from the group consisting of acyl, alkyl,alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl,thioalkoxy, and wherein R^(b) and R^(c) are fused to form a heteroarylor heterocyclic ring with the phenyl ring wherein the heteroaryl orheterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 areheteroatoms independently selected from the group consisting of oxygen,nitrogen and sulfur R^(b) and R^(b′) are independently selected from thegroup consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy,and thioalkoxy with the proviso that when R^(c) is hydrogen, then R^(b)and R^(b′) are either both hydrogen or both substituents other thanhydrogen, (c) 2-naphthyl, (d) 2-naphthyl substituted at the 4, 5, 6, 7and/or 8 positions with 1 to 5 substituents selected from the groupconsisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy,aryl, and heteroaryl, (e) heteroaryl, and (f) substituted heteroarylcontaining 1 to 3 substituents selected from the group consisting ofalkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl,thioalkoxy, thioaryloxy provided that said substituents are not ortho tothe heteroaryl attachment to the —NH group.
 7. The method according toclaim 5 wherein R¹ is selected from the group consisting of mono-, di-and tri-substituted phenyl groups.
 8. The method according to claim 7wherein R¹ is a disubstituted phenyl selected from the group consistingof 3,5-dichlorophenyl, 3,5-difluorophenyl,3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3-(trifluoromethyl)4-chlorophenyl, 3-chloro4-cyanophenyl,3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.
 9. The methodaccording to claim 7 wherein R¹ is a monosubstituted phenyl selectedfrom the group consisting of 4-azidophenyl, 4-bromophenyl,4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl,4-iodophenyl, 4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.10. The method according to claim 7 wherein R¹ is a trisubstitutedphenyl selected from the group consisting of 3,4,5-trifluorophenyl and3,4,5-trichlorophenyl.
 11. The method according to claim 5 wherein R¹ isselected from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl,benzothiazol-6-yl, 5-indolyl, and phenyl.
 12. A method according to anyof claims 1, 2 or 3 wherein m is one.
 13. A method according to claim 12wherein R¹ is selected from the group consisting of phenyl, 1-naphthyl,2-naphthyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl,2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl,4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl,4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl,4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl,3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl,3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl,2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl,3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl,3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl,n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl, pyrid-2-yl,pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl),chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl,benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl,thionaphthen-2-yl, thionaphthen-3-yl, thionaphthen-4-yl,2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thien-5-yl,6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl,2-phenyloxazol-4-yl, indol-3-yl, 1-phenyl-tetraol-5-yl, allyl,2-(cyclohexyl)ethyl, (CH₃)₂CH═CHCH₂CH₂CH(CH₃)—, φC(O)CH₂-,thien-2-yl-methyl, 2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl,2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, norboran-2-yl,(4-methoxyphenyl)methyl, (2-methoxyphenyl)methyl,(3-methoxyphenyl)methyl, (3-hydroxyphenyl)methyl,(4-hydroxyphenyl)methyl, (4-methoxyphenyl)methyl,(4-methylphenyl)methyl, (4-fluorophenyl)methyl, (4-fluorophenoxy)methyl,(2,4-dichlorophenoxy)ethyl, (4-chlorophenyl)methyl,(2-chlorophenyl)methyl, (1-phenyl)ethyl, (1-(p-chlorophenyl)ethyl,(1-trifluoromethyl)ethyl, (4methoxyphenyl)ethyl, CH₃OC(O)CH₂—,benzylthiomethyl, 5-(methoxycarbonyl)-n-pentyl,3-(methoxycarbonyl)-n-propyl, indan-2-yl, (2-methylbenzofuran-3-yl),methoxymethyl, CH₃CH═CH—, CH₃CH₂CH═CH—, (4-chlorophenyl)C(O)CH₂—,(4-fluorophenyl)C(O)CH₂—, (4-methoxyphenyl)C(O)CH₂—,4-(fluorophenyl)-NHC(O)CH₂—, 1-phenyl-n-butyl, (φ)₂CHNHC(O)CH₂CH₂—,(CH₃)₂NC(O)CH₂—, (φ)₂CHNHC(O)CH₂CH₂—, methylcarbonylmethyl,(2,4-dimethylphenyl)C(O)CH₂—, 4-methoxyphenyl-C(O)CH₂—, phenyl-C(O)CH₂—,CH₃C(O)N(φ)-, ethenyl, methylthiomethyl, (CH₃)₃CNHC(O)CH₂—,4fluorophenyl-C(O)CH₂—, diphenylmethyl, phenoxymethyl,3,4-methylenedioxyphenyl-CH₂—, benzo[b]thiophen-3-yl,(CH₃)₃COC(O)NHCH₂—, trans-styryl, H₂NC(O)CH₂CH₂—,2-trifluoromethylphenyl-C(O)CH₂, φC(O)NHCH(φ)CH₂—, mesityl,CH₃CH(═NHOH)CH₂—, 4-CH₃-φ-NHC(O)CH₂CH₂—, φC(O)CH(φ)CH₂—,(CH₃)₂CHC(O)NHCH(φ)-, CH₃CH₂OCH₂—, CH₃OC(O)CH(CH₃)(CH₂)₃—,2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH₃-benzofuran-3-yl,2-(2,4-dichlorophenoxy)ethyl, φSO₂CH₂—, 3-cyclohexyl-n-propyl,CF₃CH₂CH₂CH₂- and N-pyrrolidinyl.
 14. A method according to any ofclaims 1, 2 or 3 where n is one or two, and each R² is independentlyselected from the group consisting of alkyl, substituted alkyl, alkenyl,cycloalkyl, aryl, heteroaryl and heterocyclic.
 15. The method accordingto claim 14 wherein R² is selected from the group consisting of methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,—CH₂CH(CH₂CH₃)₂, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl,cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl,3-methylpentyl, —CH₂-cyclopropyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclohexyl, —CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl,thiophen-2-yl, —CH₂—C(O)O-t-butyl, —CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂,2-methylcyclopentyl, cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃,—CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂, —CH₂CH═CHCH₃ (cis and trans), —CH₂OH,—CH(OH)CH₃, —CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH2)4NH-Boc, —(CH2)4NH₂,—CH₂-pyridyl, pyridyl, —CH₂-naphthyl, —CH₂-(N-morpholino),p-(N-morpholino-CH₂CH₂O)-benzyl, benzo[b]thiophen-2-yl,5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-3-yl,benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl,thien-3-yl, and the like.
 16. A method according to any of claims 1, 2or 3 wherein the cyclic groups defined by W and —C(H)_(p)C(═X)— isselected from the group consisting of lactones, lactams, thiolactones,thiolactams, heterocyclic and cycloalkyl groups.
 17. The methodaccording to claim 16 wherein the cyclic group defined by W and—C(H)_(p)C(═X)—, forms a lactam or thiolactam ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 18.The method according to claim 17 wherein the lactam ring is selectedfrom the group consisting of

wherein A-B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene and —N═CH—; Q′is oxygen or sulfur; each V is independently selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; R^(b) isselected from the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl,heteroaryl, heterocyclic, and the like; R^(c) is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl;t is an integer from 0 to 4; t′ is an integer from 0 to 3; and w is aninteger from 0 to
 3. 19. The method according to claim 16 wherein thecyclic group defined by W, together with —C(H)_(p)C(═X)— is a ring ofthe formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 20.The method according to claim 19 wherein the alcohol or thiolsubstituted groups is selected from the group consisting of

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkly, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl,cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,trihalomethyl and the like; R^(a) is selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integerfrom 0 to 4; and w is an integer from 0 to
 3. 21. The method accordingto claim 16 wherein the cyclic group defined by W, together with—C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 22.The method according to claim 16 wherein the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 23.The method according to claim 22 wherein the compound of formula I isselected from the group consisting of

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl,cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,trihalomethyl and the like; R^(a) is selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integerfrom 0 to 4; and w is an integer from 0 to
 3. 24. The method accordingto claim 16 wherein the cyclic group defined by W, together with—C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alknyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 25.The method according to claim 16 wherein the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl,. cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 26.The method according to claim 16 wherein the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 27.The method according to claim 16 wherein the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 28.The method according to claim 27 wherein the compound of formula I isselected from the group consisting of:


29. The method according to claim 16 wherein the cyclic group defined byW, together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 30.The method according to claim 16 wherein the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 31.The method according to claim 16 wherein the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 32.A pharmaceutical composition comprising a pharmaceutically inert carrierand a pharmaceutically effective amount of a compound of formula I:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with—C(H)_(p)C(═X)—, forms a cycloalkyl, cycloalkenyl, heterocyclic,substituted cycloalkyl, or substituted cycloalkenyl group wherein eachof said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkylor substituted cycloalkenyl group is optionally fused to form a bi- ormulti-fused ring system (preferably no more than 5 fused rings) with oneor more ring structures selected from the group consisting ofcycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which,in turn, each of such ring structures are optionally substituted with 1to 4 substituents selected from the group consisting of hydroxyl, halo,alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro,cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino,N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substitutedalkylamino, N,N-disubstituted alkylamino, —NHC(O)R⁴, —NHSO₂R⁴, —C(O)NH₂,—C(O)NHR⁴, —C(O)NR⁴R⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NHR⁴ and —S(O)₂NR⁴R⁴where each R⁴ is independently selected from the group consisting ofalkyl, substituted alkyl, or aryl; X is selected from the groupconsisting of oxo (═O), thiooxo (═S), hydroxyl (—H, —OH), thiol (H,—SH)and hydro (H,H); Y is represented by the formula:

wherein each R² is independently selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Z isrepresented by the formula —T—CX′X″C(O)— where T is selected from thegroup consisting of a bond covalently linking R¹ to —CX′X″—, oxygen,sulfur, —NR⁵ where R⁵ is hydrogen, acyl, alkyl, aryl or heteroarylgroup; X′ is hydrogen, hydroxy or fluoro, X″ is hydrogen, hydroxy orfluoro, or X′ and X″ together form an oxo group; m is an integer equalto 0 or 1; n is an integer equal to 0, 1 or 2; p is an integer equal to0 or 1 such that when p is zero, the ring defined by W and—C(H)_(p)C(═X)— is unsaturated at the carbon atom of ring attachment toY and when p is one, the ring is saturated at the carbon atom of ringattachment to Y, with the following provisos: A. when R¹ is3,5-difluorophenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is1, then W, together with >CH and >C═X, does not form a 2-(S)-indanolgroup; B. when R¹ is phenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form atrans-2-hydroxy-cyclohex-1-yl group; C. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a gammabutyrolactone group or a5,5-dimethyl-gammabutyrolactone group; D. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a ε-caprolactam group; E. when R¹ iscyclopropyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an N-methylcaprolactamgroup; F. when R¹ is 4-chlorobenzoyl-CH₂—, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform an 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G.when R¹ is 2-phenylphenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form an7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R¹ isCH₃OC(O)CH₂—, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an2,3-dihydro-1-(t-butylC(O)CH₂-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;I. when R¹ is 4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,CH₃OC(O)CH₂—, 4-HOCH₂-phenyl, 2,4,6-trifluorophenyl,2-trifluoromethyl-4-fluorophenyl, or CH₃S—, R² is —CH₃, Z is —CH₂C(O)—,m is 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;J. when R¹ is 2,6-difluorophenyl, R² is —CH₃, Z is —CH(OH)C(O)—, m is 1,n is 1, and p is 1, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,K. when m is 1 and n is 1, then

 does not equal cycloalkyl of from 3 to 8 carbon atoms optionallysubstituted with 1 to 3 alkyl groups.
 33. The pharmaceutical compositionaccording to claim 32 where, in formula I, m is zero.
 34. Thepharmaceutical composition according to claim 33 wherein R¹ is aryl orheteroaryl.
 35. The pharmaceutical composition according to claim 34wherein R¹ is selected from the group consisting of (a) phenyl, (b) asubstituted phenyl group of the formula:

wherein R^(c) is selected from the group consisting of acyl, alkyl,alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl,thioalkoxy, and wherein R^(b) and R^(c) are fused to form a heteroarylor heterocyclic ring with the phenyl ring wherein the heteroaryl orheterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 areheteroatoms independently selected from the group consisting of oxygen,nitrogen and sulfur R^(b) and R^(b′) are independently selected from thegroup consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy,and thioalkoxy with the proviso that when R^(c) is hydrogen, then R^(b)and R^(b′) are either both hydrogen or both substituents other thanhydrogen, (c) 2-naphthyl, (d) 2-naphthyl substituted at the 4, 5, 6, 7and/or 8 positions with 1 to 5 substituents selected from the groupconsisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy,aryl, and heteroaryl, (e) heteroaryl, and (f) substituted heteroarylcontaining 1 to 3 substituents selected from the group consisting ofalkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl,thioalkoxy, thioaryloxy provided that said substituents are not ortho tothe heteroaryl attachment to the —NH group.
 36. The pharmaceuticalcomposition according to claim 32 wherein R¹ is selected from the groupconsisting of mono-, di- and tri-substituted phenyl groups.
 37. Thepharmaceutical composition according to claim 36 wherein R¹ is adisubstituted phenyl selected from the group consisting of3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di(trifluoromethyl)-phenyl,3,4-dichlorophenyl, 3,4-difluorophenyl,3-(trifluoromethyl)4chlorophenyl, 3-chloro-4-cyanophenyl,3-chloro-4-iodophenyl, and 3,4-methylenedioxyphenyl.
 38. Thepharmaceutical composition according to claim 36 wherein R¹ is amonosubstituted phenyl selected from the group consisting of4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl,4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4-(phenylcarbonyl)-phenyl,and 4-(1-ethoxy)ethylphenyl.
 39. The pharmaceutical compositionaccording to claim 36 wherein R¹ is a trisubstituted phenyl selectedfrom the group consisting of 3,4,5-trifluorophenyl and3,4,5-trichlorophenyl.
 40. The pharmaceutical composition according toclaim 32 wherein R¹ is selected from 2-naphthyl, quinolin-3-yl,2-methylquinolin-6-yl, benzothiazol-6-yl, 5-indolyl, and phenyl.
 41. Thepharmaceutical composition according to any of claim 32 wherein m isone.
 42. The pharmaceutical composition according to claim 41 wherein R¹is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl,2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 2-hydroxyphenyl,2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-phenoxyphenyl,2-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,4-nitrophenyl, 4-methylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl,4-ethoxyphenyl, 4-butoxyphenyl, 4-iso-propylphenyl, 4-phenoxyphenyl,4-trifluoromethylphenyl, 4-hydroxymethylphenyl, 3-methoxyphenyl,3-hydroxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl,3-bromophenyl, 3-phenoxyphenyl, 3-thiomethoxyphenyl, 3-methylphenyl,3-trifluoromethylphenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl,2,4-dichlorophenyl, 2,5-dimethoxyphenyl, 3,4-dichlorophenyl,3,4-difluorophenyl, 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl,3,5-difluorophenyl, 3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl,3,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl,2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,2-fluoro4-trifluoromethylphenyl, 4-benzyloxyphenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl,3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl,n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl, pyrid-2-yl,pyrid-3-yl, pyrid-4yl, fluoropyridyls, chloropyridyls, thien-2-yl,thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl,benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl,3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,1-phenyl-tetraol-5-yl, allyl, 2-(cyclohexyl)ethyl,(CH₃)₂CH═CHCH₂CH₂CH(CH₃)—, φC(O)CH₂—, thien-2-yl-methyl,2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl,(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,(3-hydroxyphenyl)methyl, (4hydroxyphenyl)methyl,(4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl,(4-fluorophenoxy)methyl, (2,4dichlorophenoxy)ethyl,(4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl,(1-p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl,(4-methoxyphenyl)ethyl, CH₃OC(O)CH₂—, benzylthiomethyl,5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl,(2-methylbenzofuran-3-yl), methoxymethyl, CH₃CH═CH—, CH₃CH₂CH═CH—,(4-chlorophenyl)C(O)CH₂—, (4-fluorophenyl)C(O)CH₂—,(4-methoxyphenyl)C(O)CH₂—, 4-(fluorophenyl)-NHC(O)CH₂—,1-phenyl-n-butyl, (φ)₂CHNHC(O)CH₂CH₂—, (CH₃)₂NC(O)CH₂—,(φ)₂CHNHC(O)CH₂CH₂—, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH₂—,4-methoxyphenyl-C(O)CH₂—, phenyl-C(O)CH₂—, CH₃C(O)N(φ)-, ethenyl,methylthiomethyl, (CH₃)₃CNHC(O)CH₂—, 4-fluorophenyl-C(O)CH₂—,diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH₂—,benzo[b]thiophen-3-yl, (CH₃)₃COC(O)NHCH₂—, trans-styryl, H₂NC(O)CH₂CH₂—,2-trifluoromethylphenyl-C(O)CH₂, φC(O)NHCH(φ)CH₂—, mesityl,CH₃CH(═NHOH)CH₂—, 4-CH₃-φ-NHC(O)CH₂CH₂—, φC(O)CH(φ)CH₂—,(CH₃)₂CHC(O)NHCH(φ)-, CH₃CH₂OCH₂—, CH₃OC(O)CH(CH₃)(CH₂)₃—,2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH₃-benzofuran-3-yl,2-(2,4-dichlorophenoxy)ethyl, φSO₂CH₂—, 3-cyclohexyl-n-propyl,CF₃CH₂CH₂CH₂— and N-pyrrolidinyl.
 43. The pharmaceutical compositionaccording to claim 32 where n is one or two, and each R² isindependently selected from the group consisting of alkyl, substitutedalkyl, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic.
 44. Thepharmaceutical composition according to claim 43 wherein R² is selectedfrom the group consisting of methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH₂CH(CH₂CH₃)₂,2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl, cyclohexyl,cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl, 3-methylpentyl,—CH₂-cyclopropyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclohexyl, —CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl, —CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl,—CH₂-C(O)O-t-butyl, —CH₂-C(CH₃)₃, —CH₂CH(CH₂CH₃)₂, 2-methylcyclopentyl,cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃, —CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂,—CH₂CH═CHCH₃ (cis and trans), —CH₂OH, —CH(OH)CH₃, —CH(O-t-butyl)CH₃,—CH₂OCH₃, —(CH₂)₄NH-Boc, —(CH₂)₄NH₂, —CH₂-pyridyl, pyridyl,—CH₂-naphthyl, —CH₂-(N-morpholino), p-(N-morpholino-CH₂CH₂O)-benzyl,benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl,4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl, thien-3-yl, and the like.45. The pharmaceutical composition according to claim 32 wherein thecyclic groups defined by W and —C(H)_(p)C(═X)— is selected from thegroup consisting of lactones, lactams, thiolactones, thiolactams,heterocyclic and cycloalkyl groups.
 46. The pharmaceutical compositionaccording to claim 45 wherein the cyclic group defined by W and—C(H)_(p)C(═X)—, forms a lactam or thiolactam ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 47.The method according to claim 46 wherein the lactam ring is selectedfrom the group consisting of

wherein A-B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene and —N═CH—; Q′is oxygen or sulfur; each V is independently selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; R^(b) isselected from the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl,heteroaryl, heterocyclic, and the like; R^(e) is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl;t is an integer from 0 to 4; t′ is an integer from 0 to 3; and w is aninteger from 0 to
 3. 48. The pharmaceutical composition according toclaim 45 wherein the cyclic group defined by W, together with—C(H)_(p)C(═X)— is a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 49.The pharmaceutical composition according to claim 48 wherein the alcoholor thiol substituted groups is selected from the group consisting of

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alky, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl,cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,trihalomethyl and the like; R^(a) is selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integerfrom 0 to 4; and w is an integer from 0 to
 3. 50. The pharmaceuticalcomposition according to claim 45 wherein the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 51.The pharmaceutical composition according to claim 45 wherein the cyclicgroup defined by W, together with —C(H)_(p)C(═X)—, forms a ring of theformula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alky, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 52.The pharmaceutical composition according to claim 51 wherein thecompound of formula I is selected from the group consisting of

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl,cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,trihalomethyl and the like; R^(a) is selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integerfrom 0 to 4; and w is an integer from 0 to
 3. 53. The pharmaceuticalcomposition according to claim 45 wherein the cyclic group defined by W,together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 54.The pharmaceutical composition according to claim 45 wherein the cyclicgroup defined by W, together with —C(H)_(p)C(═X)—, forms a ring of theformula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 55.The pharmaceutical composition according to claim 45 wherein the cyclicgroup defined by W, together with —C(H)_(p)C(═X)—, forms a ring of theformula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 56.The pharmaceutical composition according to claim 45 wherein the cyclicgroup defined by W, together with —C(H)_(p)C(═X)—, forms a ring of theformula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 57.The pharmaceutical composition according to claim 56 wherein thecompound of formula I is selected from the group consisting of:


58. The pharmaceutical composition according to claim 45 wherein thecyclic group defined by W, together with —CH)_(p)C(═X)—, forms a ring ofthe formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S—and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 59.The pharmaceutical composition according to claim 45 wherein the cyclicgroup defined by W, together with —CH)_(p)C(═X)—, forms a ring of theformula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 60.The pharmaceutical composition according to claim 45 wherein the cyclicgroup defined by W, together with —CH)_(p)C(═X)—, forms a ring of theformula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 61.A compound of formula I:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, substituted cycloalkyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic; W, together with—CH)_(p)C(═X)—, forms a cycloalkyl, cycloalkenyl, heterocyclic,substituted cycloalkyl, or substituted cycloalkenyl group wherein eachof said cycloalkyl, cycloalkenyl, heterocyclic, substituted cycloalkylor substituted cycloalkenyl group is optionally fused to form a bi- ormulti-fused ring system (preferably no more than 5 fused rings) with oneor more ring structures selected from the group consisting ofcycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl group which,in turn, each of such ring structures are optionally substituted with 1to 4 substituents selected from the group consisting of hydroxyl, halo,alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, nitro,cyano, carboxyl, carboxyl esters, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, amino, N-alkylamino,N,N-dialkylamino, N-substituted alkylamino, N-alkyl N-substitutedalkylamino, N,N-disubstituted alkylamino, —NHC(O)R⁴, —NHSO₂R⁴, —CO)NH₂,—C(O)NHR⁴, —C(O)NR⁴R⁴, —S(O)R⁴, —S(O)₂R⁴, —S(O)₂NHR⁴ and —S(O)₂NR⁴R⁴where each R⁴ is independently selected from the group consisting ofalkyl, substituted alkyl, or aryl; X is selected from the groupconsisting of oxo (═O), thiooxo (═S), hydroxyl (—H, —OH), thiol (H,—SH)and hydro (H,H); Y is represented by the formula:

wherein each R² is independently selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; Z isrepresented by the formula —T—CX′X″C(O)— where T is selected from thegroup consisting of a bond covalently linking R¹ to —CX′X″—, oxygen,Sulfur, —NR⁵ where R⁵ is hydrogen, acyl, alkyl, aryl or heteroarylgroup; X′ is hydrogen, hydroxy or fluoro, X″ is hydrogen, hydroxy orfluoro, or X′ and X″ together form an oxo group; m is an integer equalto 0 or 1; n is an integer equal to 0, 1 or 2; p is an integer equal to0 or 1 such that when p is zero, the ring defined by W and—CH)_(p)C(═X)— is unsaturated at the carbon atom of ring attachment to Yand when p is one, the ring is saturated at the carbon atom of ringattachment to Y, with the following provisos: A. when R¹ is3,5-difluorophenyl, R² is —CH₃, Z is —CH₂C(O)—, M is 1, n is 1, and p is1, then W, together with >CH and >C═X, does not form a 2-(S)-indanolgroup; B. when R¹ is phenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form atrans-2-hydroxy-cyclohex-1-yl group; C. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a gammabutyrolactone group or a5,5-dimethyl-gammabutyrolactone group; D. when R¹ is phenyl, Z is—CH₂C(O)—, m is 1, n is 0, and p is 1, then W, together with >CHand >C═X, does not form a ε-caprolactam group; E. when R¹ iscyclopropyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an N-methylcaprolactamgroup; F. when R¹ is 4-chlorobenzoyl-CH₂—, R² is —CH₃, Z is —CH₂C(O)—, mis 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform an 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one; G.when R¹ is 2-phenylphenyl, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1,and p is 1, then W, together with >CH and >C═X, does not form an7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one; H. when R¹ isCH₃OC(O)CH₂—, R² is —CH₃, Z is —CH₂C(O)—, m is 1, n is 1, and p is 1,then W, together with >CH and >C═X, does not form an2,3-dihydro-1-(t-butylC(O)CH₂-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;I. when R¹ is 4-ethoxyphenyl, 2,4,6-trimethylphenyl, 4-phenylphenyl,CH₃OC(O)CH₂—, 4-HOCH₂-phenyl, 2,4,6-trifluorophenyl,2-trifluoromethyl-4-fluorophenyl, or CH₃S—, R² is —CH₃, Z is —CH₂C(O)—,m is 1, n is 1, and p is 1, then W, together with >CH and >C═X, does notform a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one;J. when R¹ is 2,6-difluorophenyl, R² is —CH₃, Z is —CH(OH)C(O)—, m is 1,n is 1, and p is 1, then W, together with >CH and >C═X, does not form a2,3-dihydro-1-(N,N-diethylamino-CH₂CH²-)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one,K. when m is 1 and n is 1, then

 does not equal cycloalkyl of from 3 to 8 carbon atoms optionallysubstituted with 1 to 3 alkyl groups.
 62. The compound according toclaim 61 where, in formula I, m is zero.
 63. The compound according toclaim 62 wherein R¹ is aryl or heteroaryl.
 64. The compound according toclaim 63 wherein R¹ is selected from the group consisting of (a) phenyl,(b) a substituted phenyl group of the formula:

wherein R^(c) is selected from the group consisting of acyl, alkyl,alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl,thioalkoxy, and wherein R^(b) and R^(c) are fused to form a heteroarylor heterocyclic ring with the phenyl ring wherein the heteroaryl orheterocyclic ring contains from 3 to 8 atoms of which from 1 to 3 areheteroatoms independently selected from the group consisting of oxygen,nitrogen and sulfur R^(b) and R^(b′) are independently selected from thegroup consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy,and thioalkoxy with the proviso that when R^(c) is hydrogen, then R^(b)and R^(b′) are either both hydrogen or both substituents other thanhydrogen, (c) 2-naphthyl, (d) 2-naphthyl substituted at the 4, 5, 6, 7and/or 8 positions with 1 to 5 substituents selected from the groupconsisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy,aryl, and heteroaryl, (e) heteroaryl, and (f) substituted heteroarylcontaining 1 to 3 substituents selected from the group consisting ofalkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl,thioalkoxy, thioaryloxy provided that said substituents are not ortho tothe heteroaryl attachment to the —NH group.
 65. The compound accordingto claim 61 wherein R¹ is selected from the group consisting of mono-,di- and tri-substituted phenyl groups.
 66. The compound according toclaim 65 wherein R¹ is a disubstituted phenyl selected from the groupconsisting of 3,5-dichlorophenyl, 3,5-difluorophenyl,3,5-di(trifluoromethyl)-phenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3-(trifluoromethyl)4-chlorophenyl, 3-chloro4-cyanophenyl,3-chloro4-iodophenyl, and 3,4-methylenedioxyphenyl.
 67. The compoundaccording to claim 65 wherein R¹ is a monosubstituted phenyl selectedfrom the group consisting of 4-azidophenyl, 4-bromophenyl,4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl,4-iodophenyl, 4-(phenylcarbonyl)-phenyl, and 4-(1-ethoxy)ethylphenyl.68. The compound according to claim 65 wherein R¹ is a trisubstitutedphenyl selected from the group consisting of 3,4,5-trifluorophenyl and3,4,5-trichlorophenyl.
 69. The compound according to claim 61 wherein R¹is selected from 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl,benzothiazol-6-yl, 5-indolyl, and phenyl.
 70. The compound according toany of claim 61 wherein m is one.
 71. The compound according to claim 70wherein R¹ is selected from the group consisting of phenyl, 1-naphthyl,2-naphthyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl,2-hydroxyphenyl, 2-nitrophenyl, 2-methylphenyl, 2-methoxyphenyl,2-phenoxyphenyl, 2-trifluoromethylphenyl, 4-fluorophenyl,4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl,4-hydroxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl,4-iso-propylphenyl, 4-phenoxyphenyl, 4-trifluoromethylphenyl,4-hydroxymethylphenyl, 3-methoxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl,3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-phenoxyphenyl,3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl,2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl,2,5-dimethoxyphenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl,3,5-dichlorophenyl, 3,5-di-(trifluoromethyl)phenyl, 3,5-dimethoxyphenyl,2,4-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl,3,4,5-trifluorophenyl, 3,4,5-trimethoxyphenyl,3,4,5-tri-(trifluoromethyl)phenyl, 2,4,6-trifluorophenyl,2,4,6-trimethylphenyl, 2,4,6-tri-(trifluoromethyl)phenyl,2,3,5-trifluorophenyl, 2,4,5-trifluorophenyl, 2,5-difluorophenyl,2-fluoro-3-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl,2-fluoro-4-trifluoromethylphenyl, 4-benzyloxyphenyl,2-chloro-6-fluorophenyl, 2-fluoro-6-chlorophenyl,2,3,4,5,6-pentafluorophenyl, 2,5-dimethylphenyl, 4-phenylphenyl,2-fluoro-3-trifluoromethylphenyl, adamantyl, benzyl, 2-phenylethyl,3-phenyl-n-propyl, 4-phenyl-n-butyl, methyl, ethyl, n-propyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl,n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopent-1-enyl, cyclopent-2-enyl, cyclohex-1-enyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl, pyrid-2-yl,pyrid-3-yl, pyrid-4-yl, fluoropyridyls, chloropyridyls, thien-2-yl,thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl,benzofuran-2-yl, thionaphthen-2-yl, thionaphthen-3-yl,thionaphthen-4-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,2-(thiophenyl)thien-5-yl, 6-methoxythionaphthen-2-yl,3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, indol-3-yl,1-phenyl-tetraol-5-yl, allyl, 2-(cyclohexyl)ethyl,(CH₃)₂CH═CHCH₂CH₂CH(CH₃)—, φC(O)CH₂—, thien-2 -yl-methyl,2-(thien-2-yl)ethyl, 3-(thien-2-yl)-n-propyl, 2-(4-nitrophenyl)ethyl,2-(4-methoxyphenyl)ethyl, norboran-2-yl, (4-methoxyphenyl)methyl,(2-methoxyphenyl)methyl, (3-methoxyphenyl)methyl,(3-hydroxyphenyl)methyl, (4-hydroxyphenyl)methyl,(4-methoxyphenyl)methyl, (4-methylphenyl)methyl, (4-fluorophenyl)methyl,(4-fluorophenoxy)methyl, (2,4-dichlorophenoxy)ethyl,(4-chlorophenyl)methyl, (2-chlorophenyl)methyl, (1-phenyl)ethyl,(1-(p-chlorophenyl)ethyl, (1-trifluoromethyl)ethyl,(4-methoxyphenyl)ethyl, CH₃OC(O)CH₂—, benzylthiomethyl,5-(methoxycarbonyl)-n-pentyl, 3-(methoxycarbonyl)-n-propyl, indan-2-yl,(2-methylbenzofuran-3-yl), methoxymethyl, CH₃CH═CH—, CH₃CH₂CH═CH—,(4-chlorophenyl)C(O)CH₂—, (4-fluorophenyl)C(O)CH₂—,(4-methoxyphenyl)C(O)CH₂—, 4-(fluorophenyl)-NHC(O)CH₂—,1-phenyl-n-butyl, (φ)₂CHNHC(O)CH₂CH₂—, (CH₃)₂NC(O)CH₂—,(φ)₂CHNHC(O)CH₂CH₂—, methylcarbonylmethyl, (2,4-dimethylphenyl)C(O)CH₂—,4-methoxyphenyl-C(O)CH₂—, phenyl-C(O)CH₂—, CH₃C(O)N(φ)—, ethenyl,methylthiomethyl, (CH₃)₃CNHC(O)CH₂—, 4-fluorophenyl-C(O)CH₂—,diphenylmethyl, phenoxymethyl, 3,4-methylenedioxyphenyl-CH₂—,benzo[b]thiophen-3-yl, (CH₃)₃COC(O)NHCH₂—, trans-styryl, H₂NC(O)CH₂CH₂—,2-trifluoromethylphenyl-C(O)CH₂, φC(O)NHCH(φ)CH₂—, mesityl,CH₃CH(═NHOH)CH₂—, 4—CH₃-φ-NHC(O)CH₂CH₂—, φC(O)CH(φ)CH₂—,(CH₃)₂CHC(O)NHCH(φ)—, CH₃CH₂OCH₂—, CH₃OC(O)CH(CH₃)(CH₂)₃—,2,2,2-trifluoroethyl, 1-(trifluoromethyl)ethyl, 2-CH₃-benzofuran-3-yl,2-(2,4-dichlorophenoxy)ethyl, φSO₂CH₂—, 3-cyclohexyl-n-propyl,CF₃CH₂CH₂CH₂— and N-pyrrolidinyl.
 72. The compound according to claim 61where n is one or two, and each R² is independently selected from thegroup consisting of alkyl, substituted alkyl, alkenyl, cycloalkyl, aryl,heteroaryl and heterocyclic.
 73. The compound according to claim 61wherein R² is selected from the group consisting of methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,—CH₂CH(CH₂CH₃)₂, 2-methyl-n-butyl, 6-fluoro-n-hexyl, phenyl, benzyl,cyclohexyl, cyclopentyl, cycloheptyl, allyl, iso-but-2-enyl,3-methylpentyl, —CH₂-cyclopropyl, —CH₂-cyclohexyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclohexyl, —CH₂-indol-3-yl, p-(phenyl)phenyl, o-fluorophenyl,m-fluorophenyl, p-fluorophenyl, m-methoxyphenyl, p-methoxyphenyl,phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,p-(N-morpholino-CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thiophen-2-yl, —CH₂(1-methyl)cyclopropyl, —CH₂-thiophen-3-yl, thiophen-3-yl, thiophen-2-yl,—CH₂—CO)O-t-butyl, —CH₂—CCH₃)₃, —CH₂CH(CH₂CH₃)₂, 2-methylcyclopentyl,cyclohex-2-enyl, —CH[CH(CH₃)₂]COOCH₃, —CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂,—CH₂CH═CHCH₃ (cis and trans), —CH₂OH, —CH(OH)CH₃, —CH(O-t-butyl)CH₃,—CH₂OCH₃, —(CH₂)₄NH-Boc, —(CH₂)₄NH₂, —CH₂-pyridyl, pyridyl,—CH₂-naphthyl, —CH₂-(N-morpholino), p-(N-morpholino-CH₂CH₂O)-benzyl,benzo[b]thiophen-2-yl, 5-chlorobenzo[b]thiophen-2-yl,4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,6-methoxynaphth-2-yl, —CH₂CH₂SCH₃, thien-2-yl, thien-3-yl, and the like.74. The compound according to claim 61 wherein the cyclic groups definedby W and —C(H)_(p)C(═X)— is selected from the group consisting oflactones, lactams, thiolactones, thiolactams, heterocyclic andcycloalkyl groups.
 75. The compound according to claim 74 wherein thecyclic group defined by W and —C(H)_(p)C(═X)—, forms a lactam orthiolactam ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 76.The method according to claim 75 wherein the lactam ring is selectedfrom the group consisting of

wherein A-B is selected from the group consisting of alkylene,alkenylene, substituted alkylene, substituted alkenylene and —N═CH—; Q′is oxygen or sulfur; each V is independently selected from the groupconsisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy,substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, thioalkoxy, substitutedthioalkoxy, trihalomethyl and the like; R^(a) is selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,amino, carboxyl, carboxyl alkyl, cyano, halo, and the like; R^(b) isselected from the group consisting of alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, acyl, aryl,heteroaryl, heterocyclic, and the like; R^(c) is selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,aryl, heteroaryl, heterocyclic, cycloalkyl, and substituted cycloalkyl;t is an integer from 0 to 4; t′ is an integer from 0 to 3; and w is aninteger from 0 to
 3. 77. The compound according to claim 74 wherein thecyclic group defined by W, together with —C(H)_(p)C(═X)— is a ring ofthe formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 78.The compound according to claim 77 wherein the alcohol or thiolsubstituted groups is selected from the group consisting of

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl,cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,trihalomethyl and the like; R^(a) is selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integerfrom 0 to 4; and w is an integer from 0 to
 3. 79. The compound accordingto claim 74 wherein the cyclic group defined by W, together with—C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 80.The compound according to claim 74 wherein the cyclic group defined byW, together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 81.The compound according to claim 80 wherein the compound of formula I isselected from the group consisting of

wherein each V is independently selected from the group consisting ofhydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substitutedalkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl,cyano, halo, nitro, heteroaryl, thioalkoxy, substituted thioalkoxy,trihalomethyl and the like; R^(a) is selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino,carboxyl, carboxyl alkyl, cyano, halo, and the like; t is an integerfrom 0 to 4; and w is an integer from 0 to
 3. 82. The compound accordingto claim 74 wherein the cyclic group defined by W, together with—C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 83.The compound according to claim 74 wherein the cyclic group defined byW, together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 84.The compound according to claim 74 wherein the cyclic group defined byW, together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 85.The compound according to claim 74 wherein the cyclic group defined byW, together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 86.The compound according to claim 85 wherein the compound of formula I isselected from the group consisting of:


87. The compound according to claim 74 wherein the cyclic group definedby W, together with —C(H)_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 88.The compound according to claim 74 wherein the cyclic group defined byW, together with —C(H))_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 89.The compound according to claim 74 wherein the cyclic group defined byW, together with —C(H))_(p)C(═X)—, forms a ring of the formula:

wherein p is zero or one, T is selected from the group consisting ofalkylene, substituted alkylene, alkenylene, substituted alkenylene,—(R²¹Z)_(q)R₂₁— and —ZR²¹— where Z is a substituent selected from thegroup consisting of —O—, —S— and >NR²⁰, each R²⁰ is independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl,substituted alkynyl, aryl, heteroaryl and heterocyclic, each R²¹ isindependently alkylene, substituted alkylene, alkenylene and substitutedalkenylene with the proviso that when Z is —O— or —S—, any unsaturationin the alkenylene and substituted alkenylene does not involveparticipation of the —O— or —S—, and q is an integer of from 1 to
 3. 90.A compound selected from the group consisting of:1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-aminodibenzosuberane1-(R)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-(S)-indanol1-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-(R)-indanol1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-2-indanol2-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1-cyclohexanol1-(R,S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-1,2,3,4-tetrahydro-2-naphthol1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-aminobenz[f]cycloheptan-2-ol5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol1-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-aminoindan-2-one2-(N′-(phenylacetyl)-L-alaninyl)aminocyclohexan-1-one5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-γ-butyrolactone3-(N′-(3,4-dichlorophenyl)-L-alaninyl)amino-γ-butyrolactone4-(N′-(cyclopentylacetyl)-L-alaninyl)amino-1,1-dimethyl-3-isochromanone4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,1-dimethyl-3-isochromanone3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-γ-butyrolactam3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-δ-valerolactam1-benzyl-3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-δ-valerolactam3-N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-4-methyl-ε-caprolactam3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroquinolin-2-one1-benzyl-3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroquinolin-2-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-6-fluoro-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-fluoro-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-phenethyl-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-6-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-(9-aminofluroren-1-yl)glycineδ-lactam 3-(N′-(phenylacetyl)-L-alaninyl)amino-ε-caprolactam3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-ε-caprolactam3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-εcaprolactam3-(S)-N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(2-methoxyethyl)-ε-caprolactam3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-ε-caprolactam3-N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-ε-caprolactam3-N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-ethyl-ε-caprolactam3-N′-(3,5-difluorophenylacetyl)-L-alaninyl-amino)-7-benzyl-ε-caprolactam3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-4,7-methano-ε-caprolactam3-(S)-N′-(cyclopentylacetyl)-L-alaninyl)amino-1-benzyl-ε-caprolactam3-(S)-(N′-(cyclopentylacetyl)-L-phenylglycinyl)amino-1-benzyl-ε-caprolactam3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(2-phenethyl)-ε-caprolactam3(S)-N′-(cyclopentylacetyl)-L-phenylglycinyl)amino-1-(2-phenethyl)-ε-caprolactam3-(N′-(3,4-dichlorophenyl)-D,L-alaninyl)amino-ε-caprolactam3-(S)-(N′-(cyclopropylacetyl)-L-phenylglycinyl)amino-1-methyl-ε-caprolactam3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-8-octanelactam4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-2-yl)-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-3-yl)-1,2,3,4-tetrahydroisoquinolin-3-one4-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinolin-3-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-1-methyl-2-indolinone3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-methyl4-phenyl-3,4-trans-dihydrocarbostyril3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-1-methyl4-phenyl-3,4-cis-dihydrocarbostyril3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino4-phenyl-3,4-trans-dihydrocarbostyril1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-3-methyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one1-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-3-ethyl4′-fluoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-(3,5-difluorophenylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-benzyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-(N′-(cyclopentylacetyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one3-(3,5-difluorophenylacetyl)amino-1,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5-oxa-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one3-(S)-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-5-thia-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}-amino-3,3-dimethyl-5,7-dihydro-6H-benz[b]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one1-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one5-(S)-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-(S)-[N′-((S) and(R)-3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-(S)-[N′-(3,5-difluorophenyl-α-ketoacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-(S)-[N′-(3,5-difluorophenylacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-(S)-[N′-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-(S)-[N′-((S)-3,5-difluorophenyl-α-hydroxyacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-(S)-[N′-((S)-3,5-difluorophenyl-α-hydroxyacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(methoxyacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(methylcarboxylate)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(3,3-dimethyl-2-butanoyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(morpholinylacetyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-(S)-(N′-((S)-(+)-2-Hydroxy-3-methylbutyryl)-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-cyclopentyl-α-hydroxyacetyl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-(S)-(N′-((S) and(R)-3,3-dimethyl-2-hydroxybutyryl)-L-alaninyl)amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-cyclopentyl-α-hydroxyacetyl)-L-tert-leucinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-cyclopentyl-α-hydroxyacetyl)-L-alaninyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-5,7-dihydro-6H,7H-dibenz[b,d]azepin-6-one5-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-7-(2-methylpropyl)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-(2-hydroxy-3-methylbutyryl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-(S)-[N′-((S andR)-2-hydroxy-3,3-dimethylbutyryl)-L-valinyl]amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-phenyl-furazan-3-yl)alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl-}amino-7-methyl-1,2,3,4,5,7-hexahydro-6H-dicyclohexyl[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-cyclopropymethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-(2′,2′,2′-trifluoroethyl)-5,7-dihydro-H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-alaninyl}amino-7-cyclohexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}-amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-alaninyl}amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-10-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-13-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-[(S)-3,5-difluoromandelyl]-L-valinyl}amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one3-(N′-(3,4-methylenedioxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-isopropylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(ethoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-ethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(2,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorobenzoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(o-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,3-diphenylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-phenoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(indole-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-((4-methylphenoxy)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,4-dichlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-fluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(methylthio)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(methoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(phenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-phenoxybutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-(trifluoromethyl)phenylacetyl)glycinyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-butoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(2-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(isopropoxylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(1-phenyl-1H-tetrazole-5-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(3,4-methylenedioxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-cyclopentylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-cyclopentene-1-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-chloro-6-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(cyclohexylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(pentafluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,5-dimethylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-chlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(benzoylformyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,5-dimethylphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,6-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,4-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(mesitylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-biphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,4-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(trans-styrylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-benzoylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(trans-3-hexenoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(heptanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(4-methylphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(4-chlorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-phenylbutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-(4-methoxyphenyl)butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-methoxycarbonylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-phenylbutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(benzylthio)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-methylpentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(6-methoxycarbonylheptanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-indanylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-methoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,6-difluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(-(4-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(m-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-naphthylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-chlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-methylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,4-methylenedioxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-isopropylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(phenylmercaptoacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-ethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,5-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(o-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,3-diphenylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-phenoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(indole-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-phenoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-fluorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,4-dichlorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-((methylthio)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-fluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-thionaphthenacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(methoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(ethoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-indolepropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(2-chlorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(hexanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(5-phenylpentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-nitrophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(3-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(5-methylhexanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(hydrocinnamyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(octanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(3-hydroxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(4-hydroxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,4,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(5-hydantoinacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-methyl-3-Benzofuranacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(cyclopropylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-methoxypropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(5-(thienyl)pentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(4-fluorophenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(4-fluorophenoxy)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-norbornaneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,3-difluoromandelyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-pentenoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-(2,4-dichlorophenoxy)butyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,3-dichlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-(4-cyanophenoxy)-2-methylpropionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-nitrophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-fluoro-4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(4-fluorobenzoyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-((2-methylphenoxy)acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-methoxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(phenylsulfonyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-methoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(p-isopropylphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-pentenoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-hydroxyphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-oxopentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-hydroxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,4-dimethoxyphenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(4-methoxybenzoyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(thiophene-3-acetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(6-phenylhexanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(isovaleryl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,4,5-trifluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(1-adamantaneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(cyclohexanepentanoyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2-thiopheneacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-(trifluoromethyl)phenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,5-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-tolylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-fluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-bromophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3-chlorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,4-methylenedioxyphenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(phenylmercaptoacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-((methylthio)acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(phenoxyacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(phenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(cyclohexylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,5-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(benzo[b]thiophene-3-acetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(benzoylformyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,6-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(2,4-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,4-difluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(butyryl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(heptanoyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-(2-thienyl)butyryl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(5-methylhexanoyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(hydrocinnamyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(cyclopentylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(propionyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(3,4,5-trifluorophenylacetyl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one(S)-3-(N′-(4-phenylbutyryl)-L-phenylglycinyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-fluorophenylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(methylthio)acetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(methylthio)acetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(methylthio)acetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(methylthio)acetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(methylthio)acetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(methylthio)acetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(methylthio)acetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(methylthio)acetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(methylthio)acetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(phenylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(phenylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(phenylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(phenylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(phenylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(phenylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(phenylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(phenylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(phenylacetyl)-L-alaninyl)-amino-)2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(benzoylformyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(benzoylformyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(benzoylformyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(benzoylformyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(benzoylformyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(benzoylformyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(benzoylformyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(benzoylformyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(benzoylformyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(butyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(butyryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(butyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(butyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(butyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-(2-thienyl)butyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-(trifluoromethyl)butyryl)-L-alaninyl)-amino-)2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(isovaleryl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(isovaleryl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(isovaleryl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(isovaleryl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(isovaleryl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(isovaleryl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(isovaleryl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(isovaleryl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(isovaleryl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-2,3-dihydro-5-phenyl-1-(4,4,4-trifluorobutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-1-(2-oxo-2-phenylethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-1-methyl-2,3-dihydro-5-(2-thiazolyl)-1H-1,4-benzodiazepin-2-one3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-5-(2-thienyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(L-(+)-mandelyl)-L-alaninyl)amino-7-bromo-5-(2-fluorophenyl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-fluorobenzyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-ethylbutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-phenylethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-(N-phthalimidyl)ethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-biphenylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-((2-tetrahydrofuranyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-(1,4-benzodioxanyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethyl-2-oxo-propyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(ethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-pyridylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-oxo-2-(N-indolinyl)ethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(isopropyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-ethylbutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-phenylethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-(N-phthalimidyl)ethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-biphenylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethyl-2-oxo-butyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclopropylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(ethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(propyl)-1H-1,4-benzodiazepin-2-one3-(N′-(cyclopentylacetyl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(benzyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-tert-butylbenzyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-cyclohexylethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethylbutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(isopropyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(1-methoxycarbonyl-1-phenylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-ethylbutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclohexylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenylpropyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-biphenylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-(5-chlorobenzo[b]thienyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3,3-dimethyl-2-oxo-butyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(5-benzofurazanylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(3-phenoxypropyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(6-(2-trifluoromethylquinolinyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(cyclopropylmethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methylbutyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(ethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(4-(3,5-dimethylisoxazolyl)methyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(propyl)-1H-1,4-benzodiazepin-2-one3-(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino-5-phenyl-2,3-dihydro-1-(2-methoxyethyl)-1H-1,4-benzodiazepin-2-one3-(N′-(L-(+)-mandelyl)-L-alaninyl)-amino-)-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine(S)-3-(N′-(N-pyrrolidinylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-thiopheneacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-(trifluoromethyl)phenylacetic)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-(4-methoxyphenyl)propionyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(m-tolylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-fluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-bromophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(4-chlorophenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(2-naphthylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3-methylphenoxyacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[(N′-(4-methoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-ethoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-((methylthio)acetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-biphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-methoxycarbonylpropionyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,6-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(beta-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(D-3-phenyl]actyl)-L-alaninyl)amino]-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-methocyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-ethoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-((methylthio)acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-biphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-(2-thienyl)butyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,6-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(beta-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(3,3-dimethyl-2-oxobutyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-methoxyphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2-thiopheneacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(N″-acetyl-N″-phenylglycinyl)L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-bromophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(phenylmercaptoacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(cyclohexylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(pentafluorophenoxyacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(benzoylformyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3,4-difluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-(2-thienyl)butyryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(5-methylhexanoyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-fluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,5-difluoromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4,4,4-trifluorobutyryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-isopropylphenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(beta-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(mandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(4-chloromandelyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(isovaleryl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-methylthiopropionyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(L-alpha-hydroxyisocaproyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(3-nitrophenylacetyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[(N′-(D-3-phenyllactyl)-L-alaninyl)amino]-2,3-dihydro-1-(2-N,N-diethylaminoethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(3,5-difluorophenylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1.5-benzodiazepine3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-serinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(cyclopentylacetyl)-L-tyrosinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-valinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-norvalinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-methioninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-phenylalaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-(2-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-(3-thienyl)glycine]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-cyclohexylglycinyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-threoninyl]-amino-2,4-dioxo-1,5-bis-(methyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N-(4,4,4-trifluorobutryl)-L-threoninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(3,5-difluorophenylacetyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(1-piperidinyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-bromo-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-N′-methyl-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-7-chloro-2,3-dihydro-1-methyl-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-5-cyclohexyl-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-valinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-tert-leucinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-(3-fluorophenyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(4-fluorophenyl)-1H-1,4-benzodiazepin-2-one3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-valinyl]-amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1,5-dimethyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-isobutyl-5-phenyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenyl-α-oxoacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-valinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-tert-leucinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-cyclopropylmethyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenyl-α-fluoroacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-n-propyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3-methylbutyryl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(2-phenylthioacetyl)-L-phenylglycinyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3-(4-methoxyphenyl)propionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(4-cyclohexylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3-methyl-2-hydroxylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(3,3-dimethylbutryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one3-[N′-(thien-2-yl-acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-di(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,6-difluorophenyl)-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-fluorophenyl)-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,5-difluorophenyl)-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,4,6-trifluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-trifluoromethyl-4-fluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(phenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-chlorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-methyl-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-trifluoromethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-di-(trifluoromethyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-cyclomethylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,4-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-(2-thienyl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,6-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-fluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(phenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-chlorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-methylbutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-methylthiopropionyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-methyl-2-hydroxybutyryl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-nitrophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(tert-butylcarbonylmethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-methoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-thienylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-bromophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-phenylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-ethoxyphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-methylthioacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-cyclohexylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,3,4,5,6-pentafluorophenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-thionaphth-3-ylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-phenyl-2-oxoacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,4,6-trimethylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-((4-phenyl)phenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-((3,4-difluorophenyl)acetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-((4-(thien-2-yl)butyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(5-methylhexanoyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-methoxycarbonylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,6-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-fluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-hydroxymethylphenyloxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(2-trifluoromethyl-4-fluorophenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4,4,4-trifluorobutyryl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-iso-propylphenylacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3-phenyl-2-hydroxypropionyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(phenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(4-chlorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,3-dihydro-1-(2-(N,N-diethylamino)ethyl)-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-3-thienylglycinyl]amino-2,4-dioxo-1,5-bis(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1-phenyl-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2-oxo-1-methyl-5-phenyl-1,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amini-L-1H-imidazole[1,2-a]-6-phenyl-1,4-benzodiazepine4-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-L-1H-imidazole[1,2-a]-2,4-dihydro-6-phenyl-1,4-benzodiazepine4-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-L-4H[1,2,4]triazole[4,3-a]-6-phenyl-1,4-benzodiazepine3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenylacetyl)-(R)-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopropylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopentylacetyl)-R-2-thienylglycinyl]amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopropylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenylacetyl)-5-5,2-phenylglycinyl]-amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopentylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(cyclopropylmethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopentylacetyl)-L-alaninyl]amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-[N′-(cyclopentyl-α-hydroxyacetyl)-L-alaninyl]-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine3-(N′-(3,5-difluorophenylacetyl)-L-alaninyl)amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one5-{N′-(cyclopentylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-cyclopentylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclohexylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(t-butylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(hexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(heptanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{3,4-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclopropylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-cyclopentene-1-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-cyclohexylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(citronellyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-benzoylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-pentenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(valeryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-thiophenecetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-(2-thienyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-(4-nitrophenyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,4-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,6-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-isopropylphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(1-adamantaneacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclohexanepentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-((methylthio)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-thiophenepentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-norbornaneacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-3-cyclopropylalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclohexylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclopropylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-(6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(trifluoromethyl)phenylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4-difluorophenylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,4-difluorophenylacetyl)-4-ethylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-fluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclopentylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclohexylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclopropylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-thiopheneacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(trifluoromethyl)phenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-fluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,4-difluorophenylacetyl)-4-methylnorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-fluorophenylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclopentylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclohexylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclopropylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-fluorophenylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4-difluorophenylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,4-difluorophenylacetyl)-4-cyclohexylhomoalaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-fluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclopentylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclohexylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclopropylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(trifluoromethyl)phenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-fluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,4-difluorophenylacetyl)-6-fluoronorleucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-methoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(1-naphthylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4-methylenedioxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(hydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(octanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(3-hydroxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-methylphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-chlorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-hydroxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4,5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-(4-methoxyphenyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(methoxycarbonyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-phenylbutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(benzylthio)-propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-methylpentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(7-carbomethoxyheptanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-indanylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(5-carbomethoxypentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-methyl-3-Benzofuranacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-methoxypropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-fluorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-fluorophenoxy)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-pentenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-(2,4-dichlorophenoxy)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,3-dichlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-chlorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4′-fluorosuccinanilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(n-(diphenylmethyl)glutaramyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyanoacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(succinanilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,4-dichlorophenoxyaceyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(beta-propylhydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(2,4-dimethylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-fluoro-3-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,4,6-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-fluoro-2-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-fluoro-4-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-methoxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-methoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-benzyloxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-hydroxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(levulinyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-methoxybenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-phenylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-hydroxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(N-acetyl-N-phenylglycinyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(thiophene-3-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(6-phenylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(cyclohexanebutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,3,5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,4,5-trifluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(vinylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-methylthiopropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(n-tert-butylsuccinamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-bromophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-fluorobenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(o-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(p-tolylaceyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(m-tolylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4-dichlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-methylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-isopropylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(phenylmercaptoacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-ethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,5-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(o-tolylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,3-diphenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-(3-phenoxypropionyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-((4-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-phenoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4-dichlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-fluorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,4,5-trimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,4-dichlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-thianaphthenacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-[N′-(methoxyacetyl)-L-alaninyl]-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(ethoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(phenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-methoxyphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-butoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(2-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(N,N-dimethylsuccinamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(3,4-methylenedioxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-chloro-6-fluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,5-difluorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(pentafluorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-bis(trifluoromethyl)phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-dimethylphenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-chlorophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-chlorophenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(benzo[b]thiophene-3-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-dimethoxyphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,5-dimethylphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(mesitylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-biphenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(N-(tert-butoxycarbonyl)-3-aminopropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(trans-styrylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-acetamidobutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(2-chlorophenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(trans-3-hexenoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(5-phenylvaleryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(3-methoxyphenyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-chloro-beta-methylhydrocinnamyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(trifluoromethyl)butyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(alpha-naphthoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(4-phenoxybenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5{N′-(3-(2-trifluoromethylbenzoyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-benzoylamino-3-phenyl-propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-(hydroxyimino)pentanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4′-methylglutaranilyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-((4-(4-ethyl-phenoxy)-phenoxy)-acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-Benzoyl-3-phenylpropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-(hydroxymethyl)phenoxyacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4,4,4-trifluorobutyryl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-isobutyrylamino-3-phenyl-propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-((2-methylphenoxy)acetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-(phenylsulfonyl)propionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-nitrophenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3-ethoxypropionyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,3-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,6-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-fluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2,5-difluoromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(dl-beta-phenyllactyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(dl-mandelyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(p-chloromandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(1-alpha-hydroxyisocaproyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(4-bromomandelyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(1-(+)-lactyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(d-3-phenylacetyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(5-methylhexanoyl)-L-alaninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(3,5-difluorophenylacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-thiopheneacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-thiopheneacetyl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-thiopheneacetyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-thiopheneacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-thiopheneacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(2-thiopheneacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaletyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(isovaleryl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(phenylacetyl)-L-methioninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(phenylacetyl)-L-2-phenylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(phenylacetyl)-L-leucinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(phenylacetyl)-L-2-cyclohexylglycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(phenylacetyl)-L-threoninyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one5-{N′-(phenylacetyl)-L-alpha-(2-thienyl)glycinyl}-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one;and pharmaceutically acceptable salts thereof.